UNITED STATES PATENT AND TRADEMARK OFFICE
`
`APPLICATION
`NUMBER
`61/160,664
`
`FILING or
`37l(c)DATE
`03/16/2009
`
`GRPART
`UNIT
`
`FIL FEE REC'D
`220
`
`37462
`LOWRIE, LANDO & ANASTASI, LLP
`ONE MAIN STREET, SUITE 1100
`CAMBRIDGE, MA 02142
`
`Ul\TfED STATES DEPA RTME'IT OF COMMERCE
`United States Patent and Trademark Office
`Adiliess. COMMISSIO'JER FOR PATENTS
`PO Box 1450
`Alexandria, Virgmia 22313-1450
`\VVi\V.USpto.gov
`
`ATTY.DOCKET.NO
`C2081-701301
`
`TOT CLAIMS IND CLAIMS
`
`CONFIRMATION NO. 3094
`FILING RECEIPT
`
`11111111111111111 lllll ll]~!l]!~l!~l!~IIJl~!l!IIHll 11111111111111111111111
`
`Date Mailed: 05/05/2009
`
`Receipt is acknowledged of this provisional patent application. It will not be examined for patentability and will
`become abandoned not later than twelve months after its filing date. Any correspondence concerning the application
`must include the following identification information: the U.S. APPLICATION NUMBER, FILING DATE, NAME OF
`APPLICANT, and TITLE OF INVENTION. Fees transmitted by check or draft are subject to collection. Please verify
`the accuracy of the data presented on this receipt. If an error is noted on this Filing Receipt, please submit
`a written request for a Filing Receipt Correction. Please provide a copy of this Filing Receipt with the
`changes noted thereon. If you received a "Notice to File Missing Parts" for this application, please submit
`any corrections to this Filing Receipt with your reply to the Notice. When the USPTO processes the reply
`to the Notice, the USPTO will generate another Filing Receipt incorporating the requested corrections
`
`Applicant( s)
`
`Stefan Gross, Brookline, MA;
`Shengfang Jin, Newton, MA;
`Shinsan Su, Cambridge, MA;
`Valeria Fantin, Cambridge, MA;
`Power of Attorney:
`Catherine McCarty--54301
`
`If Required, Foreign Filing License Granted: 05/01/2009
`The country code and number of your priority application, to be used for filing abroad under the Paris Convention,
`is US 61 /160,664
`Projected Publication Date: None, application is not eligible for pre-grant publication
`Non-Publication Request: No
`Early Publication Request: No
`Title
`
`METHODS AND COMPOSITIONS FOR TREATING CANCER
`
`PROTECTING YOUR INVENTION OUTSIDE THE UNITED STATES
`
`Since the rights granted by a U.S. patent extend only throughout the territory of the United States and have no
`effect in a foreign country, an inventor who wishes patent protection in another country must apply for a patent
`in a specific country or in regional patent offices. Applicants may wish to consider the filing of an international
`application under the Patent Cooperation Treaty (PCT). An international (PCT) application generally has the same
`effect as a regular national patent application in each PCT-member country. The PCT process simplifies the filing
`page 1 of 3
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`of patent applications on the same invention in member countries, but does not result in a grant of "an international
`patent" and does not eliminate the need of applicants to file additional documents and fees in countries where patent
`protection is desired.
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`Almost every country has its own patent law, and a person desiring a patent in a particular country must make an
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`LICENSE FOR FOREIGN FILING UNDER
`
`Title 35, United States Code, Section 184
`
`Title 37, Code of Federal Regulations, 5.11 & 5.15
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`GRANTED
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`The applicant has been granted a license under 35 U.S.C. 184, if the phrase "IF REQUIRED, FOREIGN FILING
`LICENSE GRANTED" followed by a date appears on this form. Such licenses are issued in all applications where
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`This license is to be retained by the licensee and may be used at any time on or after the effective date thereof unless
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`The grant of a license does not in any way lessen the responsibility of a licensee for the security of the subject matter
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`State (with respect to Arms, Munitions and Implements of War (22 CFR 121-128)); the Bureau of Industry and
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`NOT GRANTED
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`No license under 35 U.S.C. 184 has been granted at this time, if the phrase "IF REQUIRED, FOREIGN FILING
`LICENSE GRANTED" DOES NOT appear on this form. Applicant may still petition for a license under 37 CFR 5.12,
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`
`page 3 of 3
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`Rigel Exhibit 1044
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`Doc Code: TR.PROV
`Document Description: Provisional Cover Sheet (SB16)
`
`PTO/SB/16 (04-07)
`Approved for use through 06/30/2010 0MB 0651-0032
`U.S. Patent and Trademark Office: U.S. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995, no persons are required to respond to a collection of information unless it displays a valid 0MB control number
`Provisional Application for Patent Cover Sheet
`This is a request for filing a PROVISIONAL APPLICATION FOR PATENT under 37 CFR 1.53(c)
`
`lnventor(s)
`
`Inventor 1
`
`Given Name
`
`Middle Name
`
`Family Name
`
`City
`
`State
`
`Stefan
`
`Inventor 2
`
`Gross
`
`Brookline
`
`MA
`
`Given Name
`
`Middle Name
`
`Family Name
`
`City
`
`State
`
`I Remove I
`Country
`
`us
`
`I Remove I
`Country
`
`Jin
`
`Newton
`
`MA
`
`us
`
`Shengfang
`
`Inventor 3
`
`Given Name
`
`Middle Name
`
`Family Name
`
`City
`
`State
`
`Shinsan
`
`Inventor 4
`
`Su
`
`Cambridge
`
`MA
`
`Given Name
`
`Middle Name
`
`Family Name
`
`City
`
`State
`
`Valeria
`
`Fantin
`
`Cambridge
`
`MA
`
`All Inventors Must Be Listed -Additional Inventor Information blocks may be
`generated within this form by selecting the Add button.
`
`I Remove I
`Country
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`us
`
`I Remove I
`Country
`
`us
`
`I Add
`
`I
`
`i
`
`i
`
`i
`
`i
`
`Title of Invention
`
`METHODS AND COMPOSITIONS FOR TREATING CANCER
`
`Attorney Docket Number (if applicable)
`
`C2081-701301
`
`Correspondence Address
`
`Direct all correspondence to (select one):
`
`0 The address corresponding to Customer Number
`
`0 Firm or Individual Name
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`Customer Number
`
`37462
`
`The invention was made by an agency of the United States Government or under a contract with an agency of the United
`States Government.
`0 No.
`0 Yes, the name of the U.S. Government agency and the Government contract number are:
`
`EFS - Web 1.0.1
`
`Rigel Exhibit 1044
`Page 4 of 95
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`

`

`Doc Code: TR.PROV
`Document Description: Provisional Cover Sheet (SB16)
`
`PTO/SB/16 (04-07)
`Approved for use through 06/30/2010 0MB 0651-0032
`U.S. Patent and Trademark Office: U.S. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995, no persons are required to respond to a collection of information unless it displays a valid 0MB control number
`
`Entity Status
`Applicant claims small entity status under 37 CFR 1.27
`0 Yes, applicant qualifies for small entity status under 37 CFR 1.27
`® No
`Warning
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`Petitioner/applicant is cautioned to avoid submitting personal information in documents filed in a patent application that may
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`
`Signature
`
`Please see 37 CFR 1.4(d} for the form of the signature.
`
`Signature
`
`/Catherine M. McCarty/
`
`Date (YYYY-MM-DD)
`
`2009-03-16
`
`First Name
`
`Catherine
`
`Last Name
`
`McCarty
`
`Registration Number
`(If appropriate)
`
`54301
`
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`form can only be used when in conjunction with EFS-Web. If this form is mailed to the USPTO, it may cause delays in handling
`the provisional application.
`
`EFS - Web 1.0.1
`
`Rigel Exhibit 1044
`Page 5 of 95
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`
`Rigel Exhibit 1044
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`C2081-701301
`
`METHODS AND COMPOSITIONS FOR TREATING CANCER
`
`The invention relates to the treatment of proliferative disorders such as cancer as
`
`well as related methods, compounds and compositions.
`
`BACKGROUND
`
`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 of NAD+.
`
`SUMMARY OF THE INVENTION
`
`The inventors have discovered novel methods for treating a proliferative disorder
`
`such as cancer. Described herein are methods, compounds and compositions for the
`
`treatment of a proliferative disorder such as cancer (e.g., a cancer of the central nervous
`
`system such as a glioma or brain tumor).
`
`In some embodiments, the methods described herein can result in reduced side
`
`effects relative to other known methods of treating cancer.
`
`In one aspect, the invention features, a method of treating a subject, e.g., a subject
`
`having a disorder characterized by unwanted cell proliferation, e.g., cancer. The method
`
`includes: administering to the subject a therapeutically effective amount of an inhibitor of
`
`a neoactivity of a mutant enzyme encoded by a mutant gene, e.g., wherein the enzyme is
`
`in a metabolic pathway, to thereby treat the subject.
`
`- 1 -
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`C2081-701301
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`In an embodiment the metabolic pathway is selected from a metabolic pathway
`
`leading to fatty acid biosynthesis, glycolysis, glutaminolysis, the pentose phosphate shunt,
`
`nucleotide biosynthetic pathways, or the fatty acid biosynthetic pathway.
`
`In another aspect, the invention provides, a method of treating a subject having
`
`cancer, e.g., a glioma or brain tumor characterized by a mutant IDHl or IDH 2 gene
`
`which encodes a mutant enzyme having a neoactivity. The method includes:
`
`administering to the subject a therapeutically effective amount of an inhibitor of
`
`the neoactivity of the mutant enzyme, wherein the neoactivity is the ability to convert
`
`alpha ketoglutarate to isocitrate, to thereby treat the subject.
`
`In another aspect, the invention features, a method of treating a subject, e.g., a
`
`subject having a disorder characterized by unwanted cell proliferation, e.g., cancer. The
`
`method includes:
`
`administering to the subject a therapeutically effective amount of a substance, or a
`
`compound that induces activity of the substance, or a compound that increases the level
`
`of said substance in vivo, wherein the subject has a mutation giving rise to a neoactivity
`
`and the endogenous level of the substance in cancer cells of the subject is reduced as
`
`compared to a cell not having the mutation, e.g., wherein the enzyme is in a metabolic
`
`pathway, to thereby treat the subject.
`
`In another aspect, the invention features, a method of treating a subject having a
`
`glioma or brain tumor characterized by a mutant IDHl or IDH2 gene which encodes a
`
`mutant enzyme having a neoactivity. The method includes:
`
`administering to the subject a therapeutically effective amount of a alpha
`
`ketogluterate, a prodrug thereof, a compound that increases the level of alpha
`
`ketogluterate in a subject, a compound that activates HIP-la hydroxylase, or a compound
`
`that inhibits HIF-1 a, to thereby treat the subject.
`
`In another aspect, the invention features, a method of evaluating a candidate
`
`compound, e.g., for use as an anti-proliferative or anti-cancer agent. The method
`
`includes:
`
`optionally supplying the candidate compound;
`
`contacting the candidate compound with an enzyme having the activity of a
`
`mutant enzyme having a neoactivity;
`
`- 2 -
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`C2081-701301
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`evaluating the ability of the candidate compound to inhibit the activity,
`
`thereby evaluating the compound.
`
`In antoher aspect the invention features, a pharmaceutical composition of an
`
`inhibitor described herein.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 depicts DNA sequence verification of pET41a-IDH1 and alignment against
`
`published IDHl CDS.
`
`FIG. 2 depicts DNA sequence verification of IDHr132s and IDHr132h mutants.
`
`FIG. 3 depicts separation of wild type IDHl protein on Ni-Sepharose column.
`
`FIG. 4 depicts protein analysis of wild type IDHl on SDS gel pre and post Ni column
`
`fractionation. T: total protein; I: insoluble fractions; S: soluble fraction; L: sample for
`
`loading on Ni-column. The numbers in the figure indicates the fraction numbers.
`
`Fractions #17 ~ #27 were collected for further purification.
`
`FIG. SA depicts separation of wild type IDHl protein through SEC column S-200.
`
`FIG. SB depicts protein analysis of wild type IDHl on SDS gel pre and post S-200
`
`column fractionation. M: molecular weight marker; Ni: nickel column fraction prior to S-
`
`200; S200: fraction from SEC column.
`
`FIG. 6 depicts separation of mutant IDH1R132S protein on Ni-Sepharose column.
`
`FIG. 7 depicts protein analysis of mutant IDH1R132S on SDS gel pre and post Ni
`
`column fractionation. M: protein marker (KDa): 116, 66.2, 45, 35, 25, 18.4, 14.4; T: total
`
`cell protein; So: soluble fraction; In: insoluble fraction; Ft: flow through. #3-#7 indicate
`
`the corresponding eluted fraction numbers.
`
`FIG. SA depicts separation of mutant IDH1R132S protein through SEC column S-200.
`
`FIG. SB depicts protein analysis of mutant IDH1R132S on SDS gel post S-200 column
`
`fractionation. M: molecular weight marker; IDHR132s: fraction from SEC column.
`
`FIG. 9 depicts separation of mutant IDH1R132H protein on Ni-Sepharose column.
`
`FIG. 10 depicts protein analysis of mutant IDH1R132H on SDS gel pre and post Ni
`
`column fractionation. M: protein marker (KDa): 116, 66.2, 45, 35, 25, 18.4, 14.4; T: total
`
`cell protein; So: soluble fraction; In: insoluble fraction; Ft: flow through; #5-#10 indicate
`
`- 3 -
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`C2081-701301
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`the corresponding eluted fraction numbers; Ni: sample from Ni-Sepharose column, pool
`
`#5-#10 together.
`
`FIG. llA depicts separation of mutant IDH1R132H protein through SEC column S-200.
`
`FIG. 11B depicts protein analysis of mutant IDH1R132H on SDS gel post S-200 column
`
`fractionation. M: molecular weight marker; IDHR132H: fraction from SEC column.
`
`FIG. 12A depicts Michalis-Menten plot of IDHl wild-type in forward reaction.
`
`FIG. 12B depicts Michalis-Menten plot of IDH1R132H mutant enzyme in forward
`
`reaction.
`
`FIG. 12C depicts Michalis-Menten plot of IDH1R132S mutant enzyme in forward
`
`reaction.
`
`FIG. 13A depicts a-KG inhibition of IDHl wild-type.
`
`FIG. 13B depicts a-KG inhibition of IDH1R132H mutant enzyme.
`
`FIG. 13C depicts a-KG inhibition of IDH1R132S mutant enzyme.
`
`FIG. 14 depicts IDHl wt, IDH R132H, and IDH R132S in the reverse reaction.
`
`FIG. lSA depicts Substrate-Concentration velocity plot for IDH R132H mutant enzyme.
`
`FIG. 15B depicts Substrate-Concentration velocity plot for IDH R132S mutant enzyme.
`
`FIG. 16 depicts IDHl wt, IDH R132H, and IDH R132S in the reverse reaction with
`
`NADH.
`
`FIG. 17A depicts oxalomalate inhibition to IDHl wt.
`
`FIG. 17B depicts oxalomalate inhibition to IDH1R132H.
`
`FIG. 17C depicts oxalomalate inhibition to IDH1R132S.
`
`DETAILED DESCRIPTION
`
`The inventors have discovered that certain mutated forms of an enzyme (e.g.,
`
`IDHl or IDH2) have a gain of function, referred to herein as a neoactivity, which can be
`
`targeted in the treatment of a proliferative disorder such as cancer. E.g., in the case of a
`
`metabolic pathway enzyme, a gain of function or neoactivity can serve as a target for
`
`treatment of cancer. Described herein are methods and compositions for the treatment of
`
`a proliferative disorder such as cancer.
`
`Neoactivity of an enzyme
`
`- 4 -
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`Rigel Exhibit 1044
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`C2081-701301
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`Neoactivity, as used herein, means an activity that arises as a result of a mutation,
`
`e.g., a point mutation, e.g., a substitution, e.g., in the active site of an enzyme. In an
`
`embodiment the neoactivity is substantially absent from wild type or non-mutant enzyme.
`
`This is sometimes referred to herein as a first degree neoactivity. An example of a first
`
`degree neoactivity is a "gain of function" wherein the mutant enzyme gains a new
`
`catalytic activity. In an embodiment the neoactivity is present in wild type or non-mutant
`
`enzyme but at a level which is less than 10, 5, 1, 0.1, 0.01 or 0.001 % of what is seen in
`
`the mutant enzyme. This is sometimes referred to herein as a second degree neoactivity.
`
`An example of a second degree neoactivity is a "gain of function" wherein the mutant
`
`enzyme has a 100 fold increase in the rate of a catalytic activity possessed by the enzyme
`
`when lacking the mutation.
`
`In some embodiments, a non-mutant form the enzyme, e.g., a wild type form,
`
`converts substance A (e.g., isocitrate) to substance B (e.g., a-ketoglutarate), and the
`
`neoactivity converts substance B (e.g., a-ketoglutarate) to substance A (e.g., isocitrate).
`
`In some embodiments, the enzyme is in a metabolic pathway, e.g., a metabolic pathway
`
`leading to fatty acid biosynthesis, glycolysis, glutaminolysis, the pentose phosphate shunt,
`
`the nucleotide biosynthetic pathway, or the fatty acid biosynthetic pathway, e.g., IDHl or
`
`IDH2.
`
`Isocitrate Dehydrogenases
`
`Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of
`
`isocitrate to 2-oxoglutarate. These enzymes belong to two distinct subclasses, one of
`
`which utilizes NAD( +) as the electron acceptor and the other NADP( + ). Five isocitrate
`
`dehydrogenases have been reported: three NAD( + )-dependent isocitrate dehydrogenases,
`
`which localize to the mitochondrial matrix, and two NADP( + )-dependent isocitrate
`
`dehydrogenases, one of which is mitochondrial and the other predominantly cytosolic.
`
`Each NADP( + )-dependent isozyme is a homodimer.
`
`IDHl (isocitrate dehydrogenase 1 (NADP+), soluble) is also known as IDH; IDP;
`
`IDCD; IDPC or PICD. The protein encoded by this gene is the NADP( + )-dependent
`
`isocitrate dehydrogenase found in the cytoplasm and peroxisomes. It contains the PTS-1
`
`peroxisomal targeting signal sequence. The presence of this enzyme in peroxisomes
`
`suggests roles in the regeneration of NADPH for intraperoxisomal reductions, such as the
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`conversion of 2, 4-dienoyl-CoAs to 3-enoyl-CoAs, as well as in peroxisomal reactions
`
`that consume 2-oxoglutarate, namely the alpha-hydroxylation of phytanic acid. The
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`cytoplasmic enzyme serves a significant role in cytoplasmic NADPH production.
`
`The human IDHl gene encodes a protein of 414 amino acids. The nucleotide and
`
`amino acid sequences for human IDHl can be found as Genebank entries NM_005896.2
`
`and NP _005887.2 respectively. The nucleotide and amino acid sequences for IDHl are
`
`also described in, e.g., Nekrutenko et al., Mol. Biol. Evol. 15:1674-1684(1998);
`
`Geisbrecht et al., J. Biol. Chem. 274:30527-30533(1999); Wiemann et al., Genome Res.
`
`11:422-435(2001); The MGC Project Team, Genome Res. 14:2121-2127(2004); Lubec et
`
`al., Submitted (DEC-2008) to UniProtKB; Kullmann et al., Submitted (JUN-1996) to the
`
`EMBL/GenBank/DDBJ databases; and Sjoeblom et al., Science 314:268-274(2006).
`
`IDH2 (isocitrate dehydrogenase 2 (NADP+ ), mitochondrial) is also known as
`
`IDH; IDP; IDHM; IDPM; ICD-M; or mNADP-IDH. The protein encoded by this gene is
`
`the NADP( + )-dependent isocitrate dehydrogenase found in the mitochondria. It plays a
`
`role in intermediary metabolism and energy production. This protein may tightly
`
`associate or interact with the pyruvate dehydrogenase complex. Human IDH2 gene
`
`encodes a protein of 452 amino acids. The nucleotide and amino acid sequences for IDH2
`
`can be found as Genebank entries NM_002168.2 and NP _002159.2 respectively. The
`
`nucleotide and amino acid sequence for human IDH2 are also described in, e.g., Huh et
`
`al., Submitted (NOV-1992) to the EMBL/GenBank/DDBJ databases; and The MGC
`
`Project Team, Genome Res. 14:2121-2127(2004).
`
`In some embodiments, non-mutant, e.g., wild type, IDHl catalyzes the oxidative
`
`decarboxylation of ioscitrate to a-ketoglutarate thereby reducing NAD+ (NADP+) to
`
`NADP (NADPH), e.g., in the forward reaction:
`
`Isocitrate + NAD+ (NADP+)-----+ a-KG+ CO2 + NADH (NADPH) + H+
`
`In some embodiments, the neoactivity of a mutant IDHl can have the ability to
`
`convert a-ketoglutarate to isocitrate, e.g., the reaction proceeds in the reverse direction:
`
`a-KG + CO2 + NADH (NADPH) + H+ -----+ Isocitrate + NAD+ (NADP+)
`
`In some embodiments, the neoactivity of a mutant IDHl can arise from a mutant
`
`IDHl having a His, Ser, Cys or Lys, or any other mutations described in Yan H et al., N
`
`Engl J Med. 2009 Feb 19;360(8):765-73, at residue 132. In some embodiments, the
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`neoactivity of a mutant IDH2 can arise from a mutant IDH2 having a Gly, Met or Lys, or
`
`any other mutations described in Yan H et al., N Engl J Med. 2009 Feb 19;360(8):765-73,
`
`at residue 172. Exemplary mutations include the following: R132H, R132C, R132S,
`
`R132G, R132L, and R132V.
`
`In some embodiments, a mutant IDHl and/or IDH2 could lead to a reduced level
`
`of a-ketoglurarate. In addition to oxygen, the praline hydroxylases that suppress HIF-1
`
`require a-ketoglurarate as a substrate. Thus, the invention includes a method of treating a
`
`subject, e.g., a subject having a disorder characterized by unwanted cell proliferation, e.g.,
`
`cancer, by administering a therapeutically effective amount of a-ketoglurarate (e.g., high
`
`levels as compared to normal metabolic conditions), an a-ketoglurarate prodrug, or a
`
`compound that increases the level of a-ketoglurarate to the subject. The cancer can be
`
`one described herein, e.g., brain tumor, e.g., glioma or brain tumor, e.g., glioblastoma,
`
`e.g., cancer having a mutant gene encoding a mutant gene product having a neoactivity, a
`
`mutant gene product having a neoactivity, or a neoactivity, by e.g., inhibiting HIF-1, e.g.,
`
`HIP-la.
`
`Methods of treating a proliferative disorder
`
`Described herein are methods of treating cancer, e.g., by inhibiting a neoactivity
`
`of a mutant enzyme, e.g., an enzyme in a metabolic pathway, e.g., a metabolic pathway
`
`leading to fatty acid biosynthesis, glycolysis, glutaminolysis, the pentose phosphate shunt,
`
`the nucleotide biosynthetic pathway, or the fatty acid biosynthetic pathway, e.g., IDHl or
`
`IDH2. The cancer can be characterized by the presence of a neoactivity, such as a gain of
`
`function in one or more mutant enzymes (e.g., an enzyme in the metabolic pathway, e.g.,
`
`a metabolic pathway leading to fatty acid biosynthesis, glycolysis, glutaminolysis, the
`
`pentose phosphate shunt, the nucleotide biosynthetic pathway, or the fatty acid
`
`biosynthetic pathway e.g., IDHl or IDH2).
`
`Described herein are methods of treating cancer by administering a substance,
`
`wherein that substance has a reduced level in vivo as a result of a neoactivity described
`
`herein. Also described herein are methods of treating cancer by administering a prodrug
`
`of the substance, a compound that increases the level of the substance in a subject, or a
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`compound that has similar activity of that substance in a subject ( e.g., activation of HIP(cid:173)
`
`la hydroxylase in a subject or inhibition of HIP-la).
`
`Proliferative disorders
`
`The disclosed methods are useful in treating proliferative disorders, e.g. treating
`
`solid tumors, soft tissue tumors, and metastases thereof wherein the solid tumor, soft
`
`tissue tumor or metastases thereof is a cancer described herein. Ex