(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`16 June 2011 (16.06.2011)
`
`PCT
`
`1111111111111111 IIIIII IIIII 111111111111111 II Ill 111111111111111 IIIII IIIII IIII IIIIIII IIII 11111111
`
`(10) International Publication Number
`WO 2011/072174 Al
`
`(51)
`
`International Patent Classification:
`A61K 31/495 (2006.01)
`C07D 243/08 (2006.01)
`A61K 31/496 (2006.01)
`C07D 405/12 (2006.01)
`A61K 31/506 (2006.01)
`A61P 35/00 (2006.01)
`A61K 31/551 (2006.01)
`
`(21) International Application Number:
`PCT /US20 I 0/059778
`
`(22) International Filing Date:
`9 December 2010 (09.12.2010)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`61/285,122
`61/313,532
`
`9 December 2009 (09.12.2009)
`12 March 2010 (12.03.2010)
`
`us (84)
`us
`(71) Applicant (for all designated States except US): AGIOS
`PHARMACEUTICALS, INC.
`[US/US]; 38 Sidney
`Street, Cambridge, MA 02139 (US).
`
`(74) Agent: MCCARTY, Catherine, M.; Lando & Anastasi,
`LLP, One Main Street, Eleventh Floor, Cambridge, MA
`02142 (US).
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,
`CA,CH,CL,CN,CO,CR,CU,CZ,DE,DK,DM,DO,
`DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT,
`HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP,
`KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD,
`ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI,
`NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD,
`SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR,
`TT, TZ, VA, VG, US, UZ, VC, VN, ZA, ZM, ZW.
`
`Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG,
`ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ,
`TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK,
`EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU,
`LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK,
`SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
`GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`
`with international search report (Art. 21 (3))
`
`(72)
`(75)
`
`Inventors; and
`(for US only): SALITURO,
`Inventors/Applicants
`Francesco, G. [US/US]; 25 Baker Drive, Marlborough,
`MA 01752 (US). SAUNDERS, Jeffrey, O. [US/US]; 117
`Seymour Street, Concord, MA 01742 (US).
`
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`(54) Title: THERAPEUTICALLY ACTIVE COMPOUNDS FOR USE IN THE TREATMENT OF CANCER CHARACTER(cid:173)
`IZED AS HAVING AN IDH MUTATION
`
`(57) Abstract: Compounds and compositions comprising compounds useful in the treatment of cancer are described herein. The
`compounds and compositions can be used to modulate an isocitrate dehydrogenase (IDH) mutant ( e.g., IDHim or IDH2m) having
`alpha hydroxyl neoactivity.
`
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`THERAPEUTICALLY ACTIVE COMPOUNDS FOR USE IN THE TREATMENT OF CANCER
`CHARACTERIZED AS HAVING AN IDH MUTATION
`
`CLAIM OF PRIORITY
`
`This application claims priority from U.S.S.N. 61/285,122, filed December 9,
`
`2009 and U.S.S.N. 61/313,532, filed March 12, 2010, each of which is incorporated
`
`herein by reference in its entirety.
`
`BACKGROUND OF INVENTION
`
`Isocitrate dehydrogenase, also known as IDH, is an enzyme which participates
`
`in the citric acid cycle. It catalyzes the third step of the cycle: the oxidative
`
`decarboxylation of isocitrate, producing alpha-ketoglutarate ( a-ketoglutarate or a-KG)
`
`and CO2 while converting NAD+ to NADH. This is a two-step process, which
`
`involves oxidation of isocitrate (a secondary alcohol) to oxalosuccinate (a ketone),
`
`followed by the decarboxylation of the carboxyl group beta to the ketone, forming
`
`alpha-ketoglutarate. Another isoform of the enzyme catalyzes the same reaction;
`
`however this reaction is unrelated to the citric acid cycle, is carried out in the cytosol
`
`as well as the mitochondrion and peroxisome, and uses NADP+ as a cofactor instead
`
`ofNAD+.
`
`It has also been discovered that a neoactivity associated with IDH mutants and
`
`that the product of the neoactivity can be significantly elevated in cancer cells. While
`
`not wishing to be bound by theory it is believed that the balance between the
`
`production and elimination of neoactive product, e.g., 2HG, e.g., R-2HG, is important
`
`in disease. Neoactive mutants can increase the level of neoactive product, while other
`
`processes, e.g., in the case of 2HG, e.g., R-2HG, enzymatic degradation of 2HG, e.g.,
`
`by 2HG dehydrogenase, reduce the level of neoative product. An incorrect balance is
`
`associated with disease. Accordingly, there is an ongoing need for modulators of IDH
`
`mutants having alpha hydroxyl neoactivity.
`
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`SUMMARY OF INVENTION
`
`Described herein are compounds, compositions (e.g., pharmaceutical
`
`compositions), and methods of treating cancer. The compounds and compositions can
`
`be used to modulate an isocitrate dehydrogenase (IDH) mutant (e.g., IDHlm or
`
`IDH2m) having alpha hydroxyl neoactivity. Also described herein are kits
`
`comprising a compound or composition of this invention.
`
`In one embodiment, disclosed herein is a compound and/or pharmaceutical
`
`composition comprising a compound of formula (I) or a pharmaceutically acceptable
`
`salt thereof:
`
`wherein:
`
`W, X, Y and Z are each independently selected from CH or N;
`B and B 1 are independently selected from hydrogen, alkyl or when taken
`
`together with the carbon to which they are attached form a carbonyl group;
`
`Q is C=O or SO2;
`D and D1 are independently selected from a bond, oxygen or NRc;
`A is aryl or heteroaryl each substituted with 0-3 occurrences of R2
`;
`R1 is independently selected from alkyl, acyl, cycloalkyl, aryl, heteroaryl,
`
`heterocyclyl, heterocyclylalkyl, cycloalkylalkyl, aralkyl, and heteroaralkyl; each of
`
`which may be optionally substituted with 0-3 occurrences of Rd;
`each R2 is independently selected from halo, hydroxy, haloalkyl, aryl,
`heteroaryl, alkyl, -NRcRc', alkyl-NRcRc', -ORa, -C(O)OH, -C(O)OR\ -C(O)NRcRc',
`
`cycloalkyl, heterocyclyl, heterocyclylalkyl, cycloalkylalkyl, aralkyl, or heteroaralkyl;
`each R3 is independently selected from halo, haloalkyl, alkyl, alkenyl, alkynyl,
`heterocyclyl and -OR a, or two adjacent R3s (when n is 2) taken together with the
`
`carbon atoms they are attached to form an optionally substituted heterocyclyl;
`
`each Ra is independently selected from alkyl, alkoxy, alkylalkoxy,
`
`alkylalkoxylalkoxy, alkyl-C(O)OR\ alkyl-C(O)OR\ and haloalkyl;
`
`2
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`each Rb is independently alkyl;
`
`each Re and Re' is independently selected from hydrogen, alkyl, alkyl(cid:173)
`
`C(O)ORb and alkenyl;
`
`each Rd is independently selected from halo, haloalkyl, alkyl, nitro, cyano, and
`
`-OR a, or two Rd taken together with the carbon atoms to which they are attached form
`
`an optionally substituted heterocyclyl;
`
`n is 0, 1, or 2;
`
`his0,1,2;and
`
`g is 0, 1 or 2.
`
`In one aspect, included is a method of treating a subject having a cell
`
`proliferation-related disorder, e.g., a precancerous disorder, or cancer, the method
`
`comprising by administering to the subject a compound or composition described
`
`herein (e.g., a compound of formula (I)), for example, a therapeutically effective
`
`amount of a compound described herein. In another aspect, included is a method of
`
`treating aciduria, e.g., 2-hydroxyglutaric aciduria, in a subject. The cell proliferation(cid:173)
`
`related disorder can be characterized by a somatic allele, e.g., a preselected allele, or
`
`mutant allele, of an IDH, e.g., IDHl or IDH2, which encodes a mutant IDH, e.g.,
`
`IDHl or IDH2, enzyme having a neoactivity.
`
`As used herein, neoactivity refers to alpha hydroxy neoactivity. Neoactivity
`
`and alpha hydroxyl neoactivity are used interchanagly herein. Alpha hydroxy
`
`neoactivity is the ability to convert an alpha ketone to an alpha hydroxy. In
`
`embodiments alpha hydroxy neoactivity proceeds with a reductive cofactor, e.g.,
`
`NADPH or NADH. In embodiments the alpha hydroxy neoactivity is 2HG
`
`neoactivity. 2HG neoactivity, as used herein, refers to the ability to convert alpha
`
`ketoglutarate to 2-hydroxyglutarate (sometimes referred to herein as 2HG), e.g., R-2-
`
`hydroxyglutarate (sometimes referred to herein as R-2HG).
`
`In an embodiment the compound (e.g., a compound of formula (I)) or
`
`composition described herein results in lowering the level of a neoactivity product,
`
`e.g., 2HG, e.g., R-2HG.
`
`3
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`In an embodiment the compound (e.g., a compound of formula (I)) or
`
`composition described herein reduces the level a neoactivity of an IDH, e.g., IDHl or
`
`IDH2, e.g., 2HG neoactivity.
`
`In an embodiment the compound (e.g., a compound of formula (I)) or
`
`composition described herein reduces the level of the product of a mutant having a
`
`neoactivity of an IDH, e.g., IDHl or IDH2 mutant, e.g., it reduces the level of 2HG,
`
`e.g., R-2HG.
`
`In an embodiment the compound described herein (e.g., a compound of
`
`formula (I)) inhibits, e.g., specifically, a neoactivity of an IDH, e.g., IDHl or IDH2,
`
`e.g., 2HG neoactivity; or inhibits both the wildtype activity and a neoactivity of an
`
`IDH, e.g., IDHl or IDH2, e.g, 2HG neoactivity.
`
`In an embodiment the IDH is IDHl and the neoactivity is 2HG neoactivity.
`
`Mutations in IDHl associated with 2HG neoactivity include mutations at residue 132,
`
`e.g., R132H or R132C.
`
`Other IDHl mutations associated with alpha hydroxy neoactivity, e.g., 2HG
`
`neoactivity include mutations at residue 71, e.g., a mutation having other than a Val at
`
`residue 71, e.g., V71I.
`
`Other IDHl mutations associated with alpha hydroxy neoactivity, e.g., 2HG
`
`neoactivity include mutations at residue 100, e.g., a mutation having other than an
`
`Arg at residue 100, and mutations at residue 109, e.g., a mutation having other than an
`
`Arg atu residue 109.
`
`In an embodiment the IDH is IDH2 and the neoactivity of the IDH2 mutant is
`
`2HG neoactivity. Mutations in IDH2 associated with 2HG neoactivity include
`
`mutations at residue 172. Mutations in IDH2 associated with 2HG neoactivity
`
`include mutations at residue 140.
`
`Treatment methods described herein can comprise evaluating a neoactivity
`
`genotype or phenotype. Methods of obtaining and analyzing samples, and the in vivo
`
`analysis in subjects, described elsewhere herein, e.g., in the section entitled, "Methods
`
`of evaluating samples and/or subjects," can be combined with this method.
`
`4
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`In an embodiment, prior to or after treatment, the method includes evaluating
`
`the growth, size, weight, invasiveness, stage or other phenotype of the cell
`
`proliferation-related disorder.
`
`In an embodiment, prior to or after treatment, the method includes evaluating
`
`the IDH, e.g., IDHl or IDH2, neoactivity genotype, e.g., 2HG genotype, or
`
`neoactivity phenotype, e.g., 2HG, e.g., R-2HG, phenotype. Evaluating the 2HG
`
`genotype can comprise determining if an IDHl or IDH2 mutation having neoactivity,
`
`e.g., 2HG neoactivity, is present, e.g., a mutation disclosed herein having neoactivity,
`
`e.g., 2HG neoactivity. Neoactivity phenotype, e.g., 2HG, e.g., R-2HG, phenotype, as
`
`used herein, refers to the level of neoactivity product (i.e., alpha hydroxyl neoactivity
`
`product), e.g., 2HG, e.g., R-2HG, level of neoactivity, e.g., 2HG neoactivity, or level
`
`of mutant IDH enzyme having neoactivity, e.g., 2HG neoactivity ( or corresponding
`
`mRNA). The evaluation can be by a method described herein.
`
`In an embodiment the subject can be evaluated, before or after treatment, to
`
`determine if the cell proliferation-related disorder is characterized by a neoactivity
`
`product, e.g., 2HG, e.g., R-2HG.
`
`In an embodiment a cancer, e.g., a glioma or brain tumor in a subject, can be
`
`analyzed, e.g., by imaging and/or spectroscopic analysis, e.g., magnetic resonance(cid:173)
`
`based analysis, e.g., MRI and/or MRS, e.g., before or after treatment, to determine if it
`
`is characterized by presence of an alpha hydroxy neoactivity product, e.g., 2HG, e.g.,
`
`R-2HG.
`
`In an embodiment the method comprises evaluating, e.g., by direct
`
`examination or evaluation of the subject, or a sample from the subject, or receiving
`
`such information about the subject, the IDH, e.g., IDHl or IDH2, genotype, or an
`
`alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG phenotype of, the subject,
`
`e.g., of a cell, e.g., a cancer cell, characterized by the cell proliferation-related
`
`disorder. (The evaluation can be, e.g., by DNA sequencing, immuno analysis,
`
`evaluation of the presence, distribution or level of an alpha hydroxy neoactivity
`
`product, e.g., 2HG, e.g., R-2HG, e.g., from spectroscopic analysis, e.g., magnetic
`
`resonance-based analysis, e.g., MRI and/or MRS measurement, sample analysis such
`
`as serum or spinal cord fluid analysis, or by analysis of surgical material, e.g., by
`
`5
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`mass-spectroscopy). In embodiments this information is used to determine or confirm
`
`that a proliferation-related disorder, e.g., a cancer, is characterized by an alpha
`
`hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG. In embodiments this
`
`information is used to determine or confirm that a cell proliferation-related disorder,
`
`e.g., a cancer, is characterized by an IDH, e.g., IDHl or IDH2, allele described herein,
`
`e.g., an IDHl allele having a mutation, e.g., a His or Cys at residue 132, or an IDH2
`
`allele having a mutation at residue 172 or residue 140.
`
`In an embodiment, before and/or after treatment has begun, the subject is
`
`evaluated or monitored by a method described herein, e.g., the analysis of the
`
`presence, distribution, or level of an alpha hydroxy neoactivity product, e.g., 2HG,
`
`e.g., R-2HG, e.g., to select, diagnose or prognose the subject, to select an inhibitor, or
`
`to evaluate response to the treatment or progression of disease.
`
`In an embodiment the cell proliferation-related disorder is a tumor of the CNS,
`
`e.g., a glioma, a leukemia, e.g., AML or ALL, e.g., B-ALL or T-ALL, prostate cancer, or
`
`myelodysplasia or myelodysplastic syndrome and the evaluation is: evaluation of the
`
`presence, distribution, or level of an alpha hydroxy neoactivity product, e.g., 2HG,
`
`e.g., R-2HG; or evaluation of the presence, distribution, or level of a neoactivity, e.g.,
`
`2HG neoactivity, of an IDHl or IDH2, mutant protein.
`
`In an embodiment, before or after treatment has begun, the genotype of an
`
`IDH mutation associated with alpha hydroxy neoactivity, e.g., 2HG neoactivity, other
`
`than a mutation at reside 132 of IDHl or other than a mutation at residue 140 or 172
`
`of IDH2, is determined.
`
`In an embodiment the presence of an IDHl mutation at residue 100 or 109 of
`
`IDHlassociated with alpha hydroxy neoactivity, e.g., 2HG neoactivity, e.g., a
`
`mutation having other than an Arg at residue 100 or 109 is determined, e.g., by
`
`sequencing genomic DNA or cDNA, from an affected cell.
`
`In an embodiment the disorder is other than a solid tumor. In an embodiment
`
`the disorder is a tumor that, at the time of diagnosis or treatment, does not have a
`
`necrotic portion. In an embodiment the disorder is a tumor in which at least 30, 40,
`
`50, 60, 70, 80 or 90% of the tumor cells carry an IHD, e.g., IDHl or IDH2, mutation
`
`having 2HG neoactivity, at the time of diagnosis or treatment.
`
`6
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`In an embodiment the cell proliferation-related disorder is a cancer, e.g., a
`
`cancer described herein, characterized by an IDHl somatic mutant having alpha
`
`hydroxy neoactivity, e.g., 2HG neoactivity, e.g., a mutant described herein. In an
`
`embodiment the tumor is characterized by increased levels of an alpha hydroxy
`
`neoactivity product, 2HG, e.g., R-2HG, as compared to non-diseased cells of the same
`
`type.
`
`In an embodiment the method comprises selecting a subject having a glioma,
`
`on the basis of the cancer being characterized by unwanted, i.e.,increased, levels of an
`
`alpha hydroxy neoactivity, product, e.g., 2HG, e.g., R-2HG.
`
`In an embodiment the cell proliferation-related disorder is a tumor of the CNS,
`
`e.g., a glioma, e.g., wherein the tumor is characterized by an IDHl somatic mutant
`
`having alpha hydroxy neoactivity, e.g., 2HG neoactivity, e.g., a mutant described
`
`herein. Gliomas include astrocytic tumors, oligodendroglial tumors, oligoastrocytic
`
`tumors, anaplastic astrocytomas, and glioblastomas. In an embodiment the tumor is
`
`characterized by increased levels of an alpha hydroxy neoactivity product, e.g., 2HG,
`
`e.g., R-2HG, as compared to non-diseased cells of the same type. E.g., in an
`
`embodiment, the IDHl allele encodes an IDHl having other than an Arg at residue
`
`132. E.g., the allele encodes His, Ser, Cys, Gly, Val, Pro or Leu, or any residue
`
`described in Yan et al., at residue 132, according to the sequence of SEQ ID N0:1
`
`(see also Fig. 1). In an embodiment the allele encodes an IDHl having His at residue
`
`132. In an embodiment the allele encodes an IDHl having Ser at residue 132.
`
`In an embodiment the IDHl allele has an A ( or any other nucleotide other than
`
`C) at nucleotide position 394, or an A ( or any other nucleotide other than G) at
`
`nucleotide position 395. In an embodiment the allele is a C394A or a G395A
`
`mutation according to the sequence of SEQ ID N0:2.
`
`In an embodiment the method comprises selecting a subject having a glioma,
`
`wherein the cancer is characterized by having an IDHl allele described herein, e.g., an
`
`IDHl allele having His or Cys at residue 132 (SEQ ID N0:1).
`
`In an embodiment the method comprises selecting a subject having a glioma,
`
`on the basis of the cancer being characterized by an IDHl allele described herein, e.g.,
`
`an IDHl allele having His or Cys at residue 132 (SEQ ID NO: 1).
`
`7
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`In an embodiment, the IDHl allele encodes an IDHl having other than a Val
`
`at residue 71, e.g., V71I.
`
`In an embodiment the method comprises selecting a subject having a glioma,
`
`wherein the cancer is characterized by having an IDHl allele described herein, e.g., an
`
`IDHl allele having Ile at residue 71 (SEQ ID NO:1).
`
`In an embodiment the method comprises selecting a subject having a glioma,
`
`on the basis of the cancer being characterized by an IDHl allele described herein, e.g.,
`
`an IDHl allele having Ile at residue 71 (SEQ ID NO:1).
`
`In an embodiment, the IDHl allele encodes an IDHl having other than an Arg
`
`at residue 109.
`
`In an embodiment the method comprises selecting a subject having a glioma,
`
`wherein the cancer is characterized by having an IDHl allele described herein, e.g., an
`
`IDHl allele other than an Arg at residue 100 or other than an Arg at residue 109
`
`In an embodiment the method comprises selecting a subject having a glioma,
`
`on the basis of the cancer being characterized by an IDHl allele described herein, e.g.,
`
`an IDHl allele having other than an Arg at residue 100 or other than an Arg at residue
`
`109.
`
`In an embodiment the method comprises selecting a subject having a glioma,
`
`on the basis of the cancer being characterized by unwanted, i.e., increased, levels of
`
`an alpha hydroxy neoactivity, product, e.g., 2HG, e.g., R-2HG.
`
`In an embodiment the cell proliferation-related disorder is localized or
`
`metastatic prostate cancer, e.g., prostate adenocarcinoma, e.g., wherein the cancer is
`
`characterized by an IDHl somatic mutant having alpha hydroxy neoactivity, e.g.,
`
`2HG neoactivity, e.g., a mutant described herein. In an embodiment the cancer is
`
`characterized by increased levels of an alpha hydroxy neoactivity product, e.g., 2HG,
`
`e.g., R-2HG, as compared to non-diseased cells of the same type.
`
`E.g., in an embodiment, the IDHl allele encodes an IDHl having other than
`
`an Arg at residue 132. E.g., the allele encodes His, Ser, Cys, Gly, Val, Pro or Leu, or
`
`any residue described in Kang et al, 2009, Int. J. Cancer, 125: 353-355 at residue 132,
`
`according to the sequence of SEQ ID NO:1 (see also FIG.1). In an embodiment the
`
`allele encodes an IDHl having His or Cys at residue 132.
`
`8
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`In an embodiment the IDHl allele has a T (or any other nucleotide other than
`
`C) at nucleotide position 394, or an A (or any other nucleotide other than G) at
`
`nucleotide position 395. In an embodiment the allele is a C394T or a G395A
`
`mutation according to the sequence of SEQ ID NO:2.
`
`In an embodiment the method comprises selecting a subject having prostate
`
`cancer, e.g., prostate adenocarcinoma, wherein the cancer is characterized by an IDHl
`
`allele described herein, e.g., an IDHl allele having His or Cys at residue 132 (SEQ ID
`
`NO:1).
`
`In an embodiment the method comprises selecting a subject having prostate
`
`cancer, e.g., prostate adenocarcinoma, on the basis of the cancer being characterized
`
`by an IDHl allele described herein, e.g., an IDHl allele having His or Cys at residue
`
`132 (SEQ ID NO:2).
`
`In an embodiment, the IDHl allele encodes an IDHl having other than a Val
`
`at residue 71, e.g., V71I.
`
`In an embodiment the method comprises selecting a subject having prostate
`
`cancer, wherein the cancer is characterized by having an IDHl allele described herein,
`
`e.g., an IDHl allele having Ile at residue 71 (SEQ ID NO:1).
`
`In an embodiment the method comprises selecting a subject having prostate
`
`cancer, on the basis of the cancer being characterized by an IDHl allele described
`
`herein, e.g., an IDHl allele having Ile at residue 71 (SEQ ID NO:1).
`
`In an embodiment, the IDHl allele encodes an IDHl having other than an Arg
`
`at residue 100 or other than an Arg at residue 109.
`
`In an embodiment the method comprises selecting a subject having prostate
`
`cancer, wherein the cancer is characterized by having an IDHl allele described herein,
`
`e.g., an IDHl allele other than an Arg at residue 100 or other than an Arg at residue
`
`109.
`
`In an embodiment the method comprises selecting a subject having prostate
`
`cancer, on the basis of the cancer being characterized by an IDHl allele described
`
`herein, e.g., an IDHl allele having other than an Arg at residue 100 or other than an
`
`Arg at residue 109.
`
`9
`
`Rigel Exhibit 1023
`Page 10 of 212
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`

`

`WO 2011/072174
`
`PCT /0S2010/059778
`
`In an embodiment the method comprises selecting a subject having prostate
`
`cancer, on the basis of the cancer being characterized by unwanted, i.e., increased,
`
`levels of an alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG.
`
`In an embodiment the cell proliferation-related disorder is a hematological
`
`cancer, e.g., a leukemia, e.g., AML, or ALL, wherein the hematological cancer is
`
`characterized by an IDHl somatic mutant having alpha hydroxy neoactivity, e.g.,
`
`2HG neoactivity, e.g., a mutant described herein. In an embodiment the cancer is
`
`characterized by increased levels of an alpha hydroxy neoactivity product, e.g., 2HG,
`
`e.g., R-2HG, as compared to non-diseased cells of the same type.
`
`In an embodiment the cell proliferation-related disorder is acute lymphoblastic
`
`leukemia (e.g., an adult or pediatric form), e.g., wherein the acute lymphoblastic
`
`leukemia (sometimes referred to herein as ALL) is characterized by an IDHl somatic
`
`mutant having alpha hydroxy neoactivity, e.g., 2HG neoactivity, e.g., a mutant
`
`described herein. The ALL can be, e.g., B-ALL or T-ALL. In an embodiment the
`
`cancer is characterized by increased levels of an alpha hydroxy neoactivity product,
`
`e.g., 2HG, e.g., R-2HG, as compared to non-diseased cells of the same type. E.g., in
`
`an embodiment, the IDHl allele is an IDHl having other than an Arg at residue 132
`
`(SEQ ID N0:1). E.g., the allele encodes His, Ser, Cys, Gly, Val, Pro or Leu, or any
`
`residue described in Kang et a.l, at residue 132, according to the sequence of SEQ ID
`
`NO: 1 (see also FIG. 1). In an embodiment the allele encodes an IDHl having Cys at
`
`residue 132.
`
`In an embodiment the IDHl allele has a T (or any other nucleotide other than
`
`C) at nucleotide position 394. In an embodiment the allele is a C394T mutation
`
`according to the sequence of SEQ ID N0:2.
`
`In an embodiment the method comprises selecting a subject having ALL, e.g.,
`
`B-ALL or T-ALL, characterized by an IDHl allele described herein, e.g., an IDHl
`
`allele having Cys at residue 132 according to the sequence of SEQ ID N0:1.
`
`In an embodiment the method comprises selecting a subject ALL, e.g.,
`
`B-ALL or T-ALL, on the basis of cancer being characterized by having an IDHl
`
`allele described herein, e.g., an IDHl allele having Cys at residue 132 (SEQ ID
`
`N0:1).
`
`Rigel Exhibit 1023
`Page 11 of 212
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`

`

`WO 2011/072174
`
`PCT /0S2010/059778
`
`In an embodiment, the IDHl allele encodes an IDHl having other than a Val
`
`at residue 71, e.g., V71I.
`
`In an embodiment the method comprises selecting a subject having ALL, e.g.,
`
`B-ALL or T-ALL, wherein the cancer is characterized by having an IDHl allele
`
`described herein, e.g., an IDHl allele having Ile at residue 71 (SEQ ID NO: 1).
`
`In an embodiment the method comprises selecting a subject having ALL, e.g.,
`
`B-ALL or T-ALL, on the basis of the cancer being characterized by an IDHl allele
`
`described herein, e.g., an IDHl allele having Ile at residue 71 (SEQ ID NO:1).
`
`In an embodiment, the IDHl allele encodes an IDHl having other than an Arg
`
`at residue 100 or other than an Arg at residue 109.
`
`In an embodiment the method comprises selecting a subject having ALL, e.g.,
`
`B-ALL or T-ALL, wherein the cancer is characterized by having an IDHl allele
`
`described herein, e.g., an IDHl allele other than an Arg at residue 100 or other than an
`
`Arg at residue 109.
`
`In an embodiment the method comprises selecting a subject having ALL, e.g.,
`
`B-ALL or T-ALL, on the basis of the cancer being characterized by an IDHl allele
`
`described herein, e.g., an IDHl allele having other than an Arg at residue 100 or other
`
`than an Arg at residue 109.
`
`In an embodiment the method comprises selecting a subject having ALL, e.g.,
`
`B-ALL or T-ALL, on the basis of the cancer being characterized by unwanted, i.e.,
`
`increased, levels of an alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG.
`
`In an embodiment the cell proliferation-related disorder is acute myelogenous
`
`leukemia (e.g., an adult or pediatric form), e.g., wherein the acute myelogenous
`
`leukemia (sometimes referred to herein as AML) is characterized by an IDHl somatic
`
`mutant having alpha hydroxy neoactivity, e.g., 2HG neoactivity, e.g., a mutant
`
`described herein. In an embodiment the cancer is characterized by increased levels of
`
`an alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG, as compared to non(cid:173)
`
`diseased cells of the same type. E.g., in an embodiment, the IDHl allele is an IDHl
`
`having other than an Arg at residue 132 (SEQ ID NO:1). E.g., the allele encodes His,
`
`Ser, Cys, Gly, Val, Pro or Leu, or any residue described in Kang et al., at residue 132,
`
`11
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`Rigel Exhibit 1023
`Page 12 of 212
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`

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`WO 2011/072174
`
`PCT /0S2010/059778
`
`according to the sequence of SEQ ID NO:1 (see also FIG.1). In an embodiment the
`
`allele encodes an IDHl having Cys at residue 132.
`
`In an embodiment the IDHl allele has a T (or any other nucleotide other than
`
`C) at nucleotide position 394. In an embodiment the allele is a C394T mutation
`
`according to the sequence of SEQ ID NO:2.
`
`In an embodiment the method comprises selecting a subject having acute
`
`myelogenous lymphoplastic leukemia (AML) characterized by an IDHl allele
`
`described herein, e.g., an IDHl allele having Cys at residue 132 according to the
`
`sequence of SEQ ID NO:1.
`
`In an embodiment the method comprises selecting a subject having acute
`
`myelogenous lymphoplastic leukemia (AML) on the basis of cancer being
`
`characterized by having an IDHl allele described herein, e.g., an IDHl allele having
`
`Cys at residue 132 (SEQ ID NO:1).
`
`In an embodiment the method comprises selecting a subject having acute
`
`myelogenous lymphoplastic leukemia (AML), on the basis of the cancer being
`
`characterized by unwanted, i.e., increased, levels of an alpha hydroxy neoactivity
`
`product, e.g., 2HG, e.g., R-2HG.
`
`In an embodiment, the IDHl allele encodes an IDHl having other than a Val
`
`at residue 71, e.g., V71I.
`
`In an embodiment the method comprises selecting a subject having AML
`
`wherein the cancer is characterized by having an IDHl allele described herein, e.g., an
`
`IDHl allele having Ile at residue 71 (SEQ ID NO:1).
`
`In an embodiment the method comprises selecting a subject having AML, on
`
`the basis of the cancer being characterized by an IDHl allele described herein, e.g., an
`
`IDHl allele having Ile at residue 71 (SEQ ID NO:1).
`
`In an embodiment, the IDHl allele encodes an IDHl having other than an Arg
`
`at residue 100 or other than an Arg at residue 109.
`
`In an embodiment the method comprises selecting a subject having AML,
`
`wherein the cancer is characterized by having an IDHl allele described herein, e.g., an
`
`IDHl allele other than an Arg at residue 100 or other than an Arg at residue 109.
`
`12
`
`Rigel Exhibit 1023
`Page 13 of 212
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`

`

`WO 2011/072174
`
`PCT /0S2010/059778
`
`In an embodiment the method comprises selecting a subject having AML, on
`
`the basis of the cancer being characterized by an IDHl allele described herein, e.g., an
`
`IDHl allele having other than an Arg at residue 100 or other than an Arg at residue
`
`109.
`
`In an embodiment the method further comprises evaluating the subject for the
`
`presence of a mutation in the NRAS or NPMc gene.
`
`In an embodiment the cell proliferation-related disorder is myelodysplasia or
`
`myelodysplastic syndrome, e.g., wherein the myelodysplasia or myelodysplastic
`
`syndrome is characterized by having an IDHl somatic mutant having alpha hydroxy
`
`neoactivity, e.g., 2HG neoactivity, e.g., a mutant described herein. In an embodiment
`
`the disorder is characterized by increased levels of an alpha hydroxy neoactivity
`
`product, e.g., 2HG, e.g., R-2HG, as compared to non-diseased cells of the same type.
`
`E.g., in an embodiment, the IDHl allele is an IDHl having other than an Arg at
`
`residue 132 (SEQ ID N0:1). E.g., the allele encodes His, Ser, Cys, Gly, Val, Pro or
`
`Leu, or any residue described in Kang et a.l, according to the sequence of SEQ ID
`
`NO: 1 (see also FIG. 1). In an embodiment the allele encodes an IDHl having Cys at
`
`residue 132.
`
`In an embodiment the IDHl allele has a T ( or any other nucleotide other than
`
`C) at nucleotide position 394. In an embodiment the allele is a C394T mutation
`
`according to the sequence of SEQ ID N0:2.
`
`In an embodiment the method comprises selecting a subject having
`
`myelodysplasia or myelodysplastic syndrome characterized by an IDHl allele
`
`described herein, e.g., an IDHl allele having Cys at residue 132 according to the
`
`sequence of SEQ ID N0:1.
`
`In an embodiment the method comprises selecting a subject having
`
`myelodysplasia or myelodysplastic syndrome on the basis of cancer being
`
`characterized by having an IDHl allele described herein, e.g., an IDHl allele having
`
`Cys at residue 132 (SEQ ID N0:1).
`
`In an embodiment, the IDHl allele encodes an IDHl having other than a Val
`
`at residue 71, e.g., V71I.
`
`13
`
`Rigel Exhibit 1023
`Page 14 of 212
`
`

`

`WO 2011/072174
`
`PCT /0S2010/059778
`
`In an embodiment the method comprises selecting a subject having
`
`myelodysplasia or myelodysplastic syndrome wherein the disorder is characterized by
`
`having an IDHl allele described herein, e.g., an IDHl allele having Ile at residue 71
`
`(SEQ ID NO:1).
`
`In an embodiment the method comprises selecting a subject having
`
`myelodysplasia or myelodysplastic syndrome, on the basis of the disorder being
`
`characterized by an IDHl allele described herein, e.g., an IDHl allele having Ile at
`
`residue 71 (SEQ ID NO:1).
`
`In an embodiment, the IDHl allele encodes an IDHl having other than an Arg
`
`at residue 100 or other than an Arg at residue 109