WO2022232417A1 - Biomarqueurs pour la réponse à des inhibiteurs de l'exportine 1 chez des patients atteints d'un myélome multiple - Google Patents

Biomarqueurs pour la réponse à des inhibiteurs de l'exportine 1 chez des patients atteints d'un myélome multiple Download PDF

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WO2022232417A1
WO2022232417A1 PCT/US2022/026766 US2022026766W WO2022232417A1 WO 2022232417 A1 WO2022232417 A1 WO 2022232417A1 US 2022026766 W US2022026766 W US 2022026766W WO 2022232417 A1 WO2022232417 A1 WO 2022232417A1
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alkyl
aryl
hydrogen
alkenyl
alkynyl
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PCT/US2022/026766
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Christopher Walker
Yosef Landesman
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Karyopharm Therapeutics Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/69—Boron compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • MM Multiple Myeloma
  • MM is a hematological malignancy characterized by the accumulation of monoclonal plasma cells in the bone marrow, the presence of monoclonal immunoglobulin, or M protein in the serum or urine, bone disease, kidney disease, and immunodeficiency.
  • MM is the second most common hematological malignancy (after non- Hodgkin’s lymphoma), representing 1% of all cancers and 2% of all cancer deaths.
  • MM has improved in the last 20 years due to the use of high-dose chemotherapy and autologous stem cell transplantation, the introduction of immunomodulatory agents, such as thalidomide, lenalidomide, and pomalidomide, and the proteasome inhibitors, bortezomib and carfilzomib.
  • immunomodulatory agents such as thalidomide, lenalidomide, and pomalidomide
  • proteasome inhibitors such as thalidomide, lenalidomide, and pomalidomide
  • bortezomib the proteasome inhibitors
  • carfilzomib carfilzomib
  • the present invention is a method of treating multiple myeloma (MM) in a subject in need thereof, comprising the steps of: obtaining a sample from the subject; determining the presence or absence of one or more RAS mutations in the sample; and administering a therapeutically effective amount of a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof: [0005] and one or more of an additional therapeutic agent to the subject determined to have one or more RAS mutations present.
  • MM multiple myeloma
  • Ring A is phenyl or pyridyl;
  • X is -N- or -C(H)-;
  • each R 1 is independently selected from -CN, halo, - OH, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 3-18 membered heterocycloalkyl, halo- C 1 -C 4 alkyl, -NH 2 , -NO 2 , -NH(C 1 -C 4 alkyl), -N(C 1 -C 3 alkyl)(C 1 -C 3 alkyl), -C(O)OH, -C(O)O-(C 1 - C 6 alkyl), -C(O)-(C 1 -C 4 alkyl), -O-(C 1 -C 4 alkyl), -O-(C 1 -C 4 haloalkyl), and -S-( C 1 -C 4 alkyl);
  • R 2 is
  • R 5 , R 6 and R 6 are each independently selected from hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 18 carbocyclyl, C 6 -C 18 aryl, 3-18-membered heterocyclyl and 5-18- membered heteroaryl; or R 5 and R 6 or R 5 and R 6 are each independently taken together with the nitrogen atom to which they are commonly attached to form a 3-18-membered heterocyclyl or 5-18-membered heteroaryl; each R 7 and R 7’ are each independently hydrogen or C 1 -C 4 alkyl; and n is 0, 1, 2, 3, 4 or 5; wherein, unless otherwise designated, each alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, aryl, cycloalkyl, heterocyclyl and heteroaryl is optionally and independently substituted.
  • the present invention is a method of treating multiple myeloma in a subject in need thereof.
  • the method comprises administering a therapeutically effective amount of a compound represented by structural formula (I) [0009] or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents, wherein the subject is determined to have a one or more RAS mutation.
  • structural formula (I) is defined above.
  • the present invention is a method of selecting and treating a subject suffering from multiple myeloma (MM), comprising the steps of: selecting the subject only if the subject has been determined to have one or more RAS mutations; and administering to the selected subject a therapeutically effective amount of a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof,
  • the present invention is a method of treating multiple myeloma in a subject in need thereof, comprising the steps of: receiving information about the absence or presence of one or more RAS mutation in the subject; and administering a therapeutically effective amount of a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof
  • the present invention is a use of an XPOl inhibitor described herein or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents for treating multiple myeloma in a subject in need thereof, wherein the subject has been determined to have one or more RAS mutations.
  • the present invention is a use of an XPOl inhibitor described herein and one or more additional therapeutic agents for the manufacture of a medicament for treating multiple myeloma in a subject determined to have one or more RAS mutations.
  • FIG. 1 A depicts superimposed plots of progression-free survival as a function of time (months) for MM patients, either Ras mut or Ras wt , where the patients enrolled in the STORM trial receive the XPOl inhibitor selinexor in combination with the steroid dexamethasone.
  • FIG. IB depicts superimposed plots of overall survival as a function of time for MM patients, either Ras mut or Ras wt , where the patients enrolled on the STORM trial received the XPOl inhibitor selinexor in combination with the steroid dexamethasone.
  • FIG. 2A depicts superimposed plots of progression-free survival as a function of time for Ras mut MM patients enrolled on the BOSTON trial who either received or did not receive an XPOl inhibitor selinexor, in combination with the proteasome inhibitor bortezomib and the steroid dexamethasone.
  • FIG. 2B depicts superimposed plots of progression-free survival as a function of time for MM patients, either Ras mut or Ras wt , where the patients enrolled on the BOSTON trial received an XPOl inhibitor selinexor, in combination with the proteasome inhibitor bortezomib and the steroid dexamethasone.
  • FIG. 2C depicts superimposed plots of progression-free survival as a function of time for MM patients, either Ras mut or Ras wt , where the patients enrolled on the BOSTON trial did not received an XPOl inhibitor selinexor, but were treated with the proteasome inhibitor bortezomib and the steroid dexamethasone.
  • FIG. 2D depicts superimposed plots of overall survival as a function of time for MM patients, either Ras mut or Ras wt , where the patients enrolled on the BOSTON trial received an XPOl inhibitor selinexor, in combination with the proteasome inhibitor bortezomib and the steroid dexamethasone.
  • FIG. 2E depicts superimposed plots of overall survival as a function of time for MM patients, either Ras mut or Ras wt , where the patients enrolled on the BOSTON trial did not received an XPOl inhibitor selinexor, but were treated with the proteasome inhibitor bortezomib and the steroid dexamethasone.
  • Targeting exportin 1 is a promising therapeutic option for patients with multiple myeloma (MM).
  • exemplary XPOl inhibitors useful for practicing the present invention are compounds represented by structural formula (I): wherein:
  • Ring A is phenyl or pyridyl
  • X is -N- or -C(H)-; each R 1 is independently selected from -CN, halo, - OH, C 1 -C 4 alkyl, C 3 - C 6 cycloalkyl, 3-18 membered heterocycloalkyl, halo-C 1 -C 4 alkyl, -NH 2 , -NO 2 , -NH(C 1 -C 4 alkyl), -N(C 1 -C 3 alkyl)(C 1 -C 3 alkyl), -C(O)OH, -C(O)O-(C 1 -C 6 alkyl), -C(O)-(C 1 -C 4 alkyl), -O-(C 1 -C 4 alkyl), -O-(C 1 -C 4 haloalkyl), and -S-( C 1 -C 4 alkyl);
  • R 2 is selected from -C(O)-O-R 3 , -C(O)-N(R 5 )(R 6 ), -C(O)-N(R 7 )-N(R 5 )(R 6 ),
  • R a is hydrogen and R b is selected from hydrogen, -C(O)-O-R 3’ , -C(O)-N(R 5’ )(R 6’ ), -C(O)-N(R 7’’ )-N(R 5’ )(R 6’ ), -CN, -C(S)-O-R 3’ , -C( S)-N(R 5 )(R 6 ), -C(S)-N(R 7’ )-N(R 5 )(R 6 ), and 5-18-membered heteroaryl, wherein:
  • R 3 and R 3 are each independently selected from C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 18 carbocyclyl, C 6 -C 18 aryl, 3-18-membered heterocyclyl and 5-18-membered heteroaryl;
  • R 5 , R 5 , R 6 and R 6 are each independently selected from hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 18 carbocyclyl, C 6 -C 18 aryl, 3-18-membered heterocyclyl and 5- 18-membered heteroaryl; or
  • R 5 and R 6 or R 5 and R 6 are each independently taken together with the nitrogen atom to which they are commonly attached to form a 3-18-membered heterocyclyl or 5-18- membered heteroaryl;
  • each R 7 and R 7’’ are each independently hydrogen or C 1 -C 4 alkyl; and [0030] n is 0, 1, 2, 3, 4 or 5;
  • each alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, aryl, cycloalkyl, heterocyclyl (heterocycloalkyl) and heteroaryl is optionally and independently substituted on any substitutable position (e.g., optional substituents can be present at 1, 2, 3, 4 or 5 positions).
  • each R 7 or R7' is hydrogen.
  • the values for the remaining variables are as defined with respect to structural formula I.
  • X is -C(H)-.
  • the values for the remaining variables are as defined with respect to structural formula I, or first aspect thereof.
  • X is -N-.
  • the values for the remaining variables are as defined with respect to structural formula I, or first or second aspect thereof.
  • n is 0, 1 or 2.
  • the values for the remaining variables are as defined with respect to structural formula I, or first through third aspects thereof.
  • each R 1 is independently selected from halo, -C 1 -C 4 alkyl, -C 1 -C 4 haloalkyl, and -O-C 1 -C 4 alkyl, or is absent. The values for the remaining variables are as defined with respect to structural formula I, or first through fourth aspects thereof.
  • each R 1 is independently selected from -CF 3 , -Cl and -OCH3, or is absent. The values for the remaining variables are as defined with respect to structural formula I, or first through fifth aspects thereof.
  • R 2 is -C(O)-O-R 3 , and R 3 is selected from optionally substituted C 1 -C 4 alkyl and optionally substituted C 2 -C 4 alkenyl; or
  • R 2 is -C(O)-N(R 5 )(R 6 ), and R 5 and R 6 are taken together with the nitrogen atom to which they are commonly attached to form an optionally substituted saturated 3- 18-membered heterocyclyl; or
  • R 2 is -C(O)-NH-NH(R 6 ), and R 6 is an optionally substituted 5-18-membered heteroaryl; or
  • R 2 is optionally substituted 5-6-membered heteroaryl.
  • the values for the remaining variables are as defined with respect to structural formula I, or first through sixth aspects thereof.
  • R 2 is -C(O)-N(R 5 )(R 6 ), and R 5 and R 6 are taken together with the nitrogen atom to which they are commonly attached to form an optionally substituted azetidin-l-yl, pyrrolidin-l-yl, or piperidin-l-yl; or
  • R 2 is -C(O)-NH-NH(R 6 ), and R 6 is optionally substituted pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; or
  • R 2 is optionally substituted oxadiazolyl.
  • the values for the remaining variables are as defined with respect to structural formula I, or first through seventh aspects thereof.
  • R 2 is selected from -C(O)-O-R 3 , -C(O)-N(R 5 )(R 6 ), -C(O)-N(R 7 )-N(R 5 )(R 6 ), and 5-18-membered heteroaryl.
  • the values for the remaining variables are as defined with respect to structural formula I, or first through sixth aspects thereof.
  • Ring A is phenyl.
  • the values for the remaining variables are as defined with respect to structural formula I, or first through ninth aspects thereof.
  • Ring A is pyridyl.
  • Ring A is pyrid-2-yl, pyrid-3-yl or pyrid-4-yl.
  • the values for the remaining variables are as defined with respect to structural formula I, or first through ninth and eleventh aspects thereof.
  • Ring A is pyrid-4-yl.
  • the values for the remaining variables are as defined with respect to structural formula I, or first through ninth, eleventh and twelfth aspects thereof.
  • R 2 is -C(O)-O-R 3
  • R 3 is selected from unsubstituted C 1 -C 4 alkyl, Ci alkyl substituted with a 5-6-membered monocyclic heterocyclyl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and C 2 -C 4 alkenyl; or
  • R 2 is -C(O)-N(R 5 )(R 6 ), and R 5 and R 6 are taken together with the nitrogen atom to which they are commonly attached to form an optionally substituted saturated 3- 18-membered heterocyclyl; or
  • R 2 is -C(O)-NH-NH(R 6 ), and R 6 is an optionally substituted 5-18-membered heteroaryl; or
  • R 2 is optionally substituted 5-6-membered heteroaryl.
  • the values for the remaining variables are as defined with respect to structural formula I, or first through sixth and ninth through thirteenth aspects thereof.
  • R b is hydrogen.
  • the compounds of structural formula I are represented by structural formula (II): [0048] or a pharmaceutically acceptable salt thereof.
  • the values for the variables and optional substituents on each alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, aryl, cycloalkyl, heterocyclyl (heterocycloalkyl) and heteroaryl are as defined with respect to structural formula I, or any aspect thereof.
  • each alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, aryl, cycloalkyl, heterocyclyl (heterocycloalkyl) and heteroaryl is optionally and independently substituted on any substitutable position (e.g., optional substituents can be present at 1, 2, 3, 4 or 5 positions).
  • each R 1a and R 1b is independently selected from -CN, halo, - OH, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 3-18 membered heterocycloalkyl, halo-C 1 -C 4 alkyl, -NH 2 , -NO 2 , -NH(C 1 -C 4 alkyl), -N(C 1 -C 3 alkyl)(C 1 -C 3 alkyl), -C(O)OH, -C(O)O-(C 1 -C 6 alkyl), -C(O)-(C 1 -C 4 alkyl), -O-(C 1 -C 4 alkyl), -O-(C 1 -C 4 haloalkyl), and -S-( C 1 -C 4 alkyl); and m is independently selected from -CN, halo, - OH, C 1 -C 4 alkyl, C 3 -C
  • R 1a is halo or -C 1 -C 4 haloalkyl.
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • R 1b is -C 1 -C 4 haloalkyl or -O-C 1 - C 4 alkyl, or is absent.
  • the values for the remaining variables are as defined above for the structural formula I or any aspect thereof.
  • m is 0.
  • the values for the remaining variables are as defined above for structural formula I, or any aspect thereof.
  • m is 1.
  • the values for the remaining variables are as defined above for structural formula I, or any aspect thereof.
  • R 1a and R 1b are each independently selected from -CF 3 , -CN, halo, - OH, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 1 2 heterocycloalkyl, halo-C 1 -C 3 alkyl, -NH 2 , -NO 2 , -NH(C 1 -C 3 alkyl), -N(C 1 -C 3 alkyl)(C 1 -C 3 alkyl), -C(O)OH, -C(O)O-(C 1 -C 6 alkyl), -C(O)-(C 1 -C 3 alkyl), -O-(C 1 -C 3 alkyl), -O-(C 1 -C 3 haloalkyl), and -S-( C 1 -C 3 alkyl).
  • the values for the remaining variables are as defined above for structural
  • R 1a and R 1b are each -CF 3 .
  • the values for the remaining variables are as defined above for structural formula I, or any of aspects one through four and seventh through sixth thereof.
  • R 2 is -C(O)-O-R 3
  • R 3 is selected from unsubstituted C 1 -C 4 alkyl, Ci alkyl substituted with a 5-6-membered monocyclic heterocyclyl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and C 2 -C 4 alkenyl; or
  • R 2 is -C(O)-N(R 5 )(R 6 ), and R 5 and R 6 are taken together with the nitrogen atom to which they are commonly attached to form an optionally substituted saturated 3- 18-membered heterocyclyl; or
  • R 2 is -C(O)-NH-NH(R 6 ), and R 6 is an optionally substituted 5-18-membered heteroaryl; or
  • R 2 is optionally substituted 5-6-membered heteroaryl.
  • the values for the remaining variables are as defined above for structural formula I, or any of the first through sixth and ninth through thirteenth aspects thereof.
  • R b is hydrogen.
  • R 2 is an optionally substituted 5-18-membered heteroaryl, wherein: optionally substitution is on on any substitutable position (e.g., optional substituents can be present at 1, 2, 3, 4 or 5 positions).
  • R 2 is an optionally substituted 5- 6-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • R 2 is an optionally substituted
  • 5-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • R 2 is an optionally substituted pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, or oxadiazolyl.
  • R 2 is an optionally substituted
  • 6-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • R 2 is an optionally substituted pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl ortriazinyl.
  • substituents independently selected from halogen, C 1 -C 4 alkyl, halo-C 1 -C 4 alkyl, C 1 - C 4 alkoxy, halo-C 1 -C 4 alkoxy, C 1 -C 4 thioalkoxy, hydroxyl, amino, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, sul
  • R 2 is optionally substituted with halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or oxo.
  • R 2 is optionally substituted with 1, 2 or 3 substituents independently selected from fluoro, chloro, C 1 -C 4 alkyl, -CF 3 , amino, oxo and cyano.
  • R 5 and R 6 are each independently selected from hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 18 carbocyclyl, C 6 -C 18 aryl, 3-18-membered heterocyclyl and 5-18- membered heteroaryl; or
  • R 5 and R 6 are taken together with the nitrogen atom to which they are commonly attached to form a 3-18-membered heterocyclyl or 5-18-membred heteroaryl, wherein, unless otherwise designated, each alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl (heterocycloalkyl) and heteroaryl is optionally and independently substituted on any substitutable position (e.g., optional substituents can be present at 1, 2, 3, 4 or 5 positions).
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • R 5 is hydrogen or methyl and R 6 is an optionally substituted 5-6-membered heteroaryl; or R 5 and R 6 are taken together with the nitrogen atom to which they are commonly attached to form an optionally substituted 4-7-membered heterocyclyl.
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • R 5 is hydrogen or methyl and R 6 is an optionally substituted 5-6-membered heteroaryl having at least one nitrogen atom and, optionally, 1-3 additional heteroatoms selected from nitrogen, oxygen and sulfur; or R 5 and R 6 are taken together with the nitrogen atom to which they are commonly attached to form an optionally substituted 4-6-membered heterocyclyl.
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • R 5 is hydrogen or methyl and R 6 is an optionally substituted 5-6-membered heteroaryl having 1-3 nitrogen atoms; or R 5 and R 6 are taken together with the nitrogen atom to which they are commonly attached to form an optionally substituted 4-6-membered heterocyclyl.
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • R 5 is methyl. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • R 5 is hydrogen.
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • R 5 is selected from hydrogen and methyl and R 6 is selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazin-2-yl, and quinoxalin-2-yl, pyrimidin-4-yl, l,l-dioxotetrahydrothiophen-3-yl and cyclopropyl and is optionally substituted with one or more substituents independently selected from methyl and halogen.
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • R 5 is selected from hydrogen and methyl and R 6 is selected from pyridin-2-yl, pyridin-4-yl, pyrazin-2-yl and pyrimidin-4-yl and is optionally substituted with a single substituent selected from methyl and chloro.
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • R 5 is selected from hydrogen and R 6 is selected from pyridin-2-yl and pyrazin-2-yl and is optionally substituted with one or more substituents independently selected from methyl, halogen and oxo.
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • R 5 is selected from hydrogen and R 6 is selected from pyrazin-2-yl and is optionally substituted with one or more substituents independently selected from methyl, halogen and oxo.
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • R 5 is selected from hydrogen and R 6 is selected from pyridine-2-yl and is optionally substituted with one or more substituents independently selected from methyl, halogen and oxo.
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • the substituent is oxo.
  • R 5 and R 6 are taken together with the nitrogen atom to which they are commonly attached to form a 3-18-membered heterocyclyl, wherein, unless otherwise designated, each alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl (heterocycloalkyl) and heteroaryl is optionally and independently substituted on any substitutable position (e.g., optional substituents can be present at 1, 2, 3, 4 or 5 positions).
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • R 5 and R 6 are taken together with the nitrogen atom to which they are commonly attached to form 6-membered heterocyclyl wherein, unless otherwise designated, each alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl (heterocycloalkyl) and heteroaryl is optionally and independently substituted on any substitutable position (e.g., optional substituents can be present at 1, 2, 3, 4 or 5 positions).
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • the 6-membered heterocyclyl is substituted on any substitutable position (e.g., optional substituents can be present at 1, 2, 3 or 4 positions including the hetero
  • Exemplary compounds for use in the methods of the invention are set forth in Tables 1 A, IB, IC and IF. Methods of making compounds disclosed in Table 1 A and compounds of formula (I) wherein R 2 is -C(O)-O-R 3 are disclosed, for example, in International Application No. PCT/US2011/027328, the entire contents of which are incorporated herein by reference.
  • Table 1A Exemplary Compounds. [0083] Table 1A. Exemplary Compounds (Cont.). -
  • the compound is selected from referred to herein selinexor or XPOVIO referred to herein as verdinexor
  • the compound is selected from:
  • the compound i referred to herein as eltanexor the compound i referred to herein as eltanexor.
  • aliphatic or “aliphatic group,” as used herein, denotes a monovalent hydrocarbon radical that is straight-chain (i.e., unbranched), branched, or cyclic (including fused, bridged, and spiro-fused polycyclic).
  • An aliphatic group can be saturated or can contain one or more units of unsaturation, but is not aromatic. Unless otherwise specified, aliphatic groups contain 1-6 carbon atoms. However, in some embodiments, an aliphatic group contains 1-10 or 2-8 carbon atoms.
  • aliphatic groups contain 1- 4 carbon atoms and, in yet other embodiments, aliphatic groups contain 1-3 carbon atoms.
  • Suitable aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • An aliphatic group can be optionally substituted as described herein.
  • alkyl as used herein, means a saturated, straight-chain or branched aliphatic group. In one aspect, an alkyl group contains 1-6 or 1-4 carbon atoms.
  • Alkyl includes, but is not limited to, methyl, ethyl, propyl, iso-propyl, n-butyl, sec-butyl, t-butyl, and the like.
  • An alkyl group can be optionally substituted as described herein.
  • an alkenyl group has from two to four carbon atoms, and includes, for example, and without being limited thereto, ethenyl, 1-propenyl, 1-butenyl and the like.
  • alkenyl encompasses radicals having carbon-carbon double bonds in the “cis” and “trans” or, alternatively, the “E” and “Z” configurations. If an alkenyl group includes more than one carbon-carbon double bond, each carbon-carbon double bond is independently a cis or trans double bond, or a mixture thereof.
  • An alkenyl group can be optionally substituted as described herein.
  • alkynyl means a straight-chain or branched aliphatic radical having one or more carbon-carbon triple bonds (i.e., -C ⁇ C-).
  • an alkyl group has from two to four carbon atoms, and includes, for example, and without being limited thereto, 1-propynyl (propargyl), 1-butynyl and the like.
  • An alkynyl group can be optionally substituted as described herein.
  • cycloaliphatic refers to a saturated or partially unsaturated cyclic aliphatic monocyclic or bicyclic ring system, as described herein, having from 3 to 12 members, wherein the aliphatic ring system is optionally substituted as defined above and described herein.
  • a cycloaliphatic group has 3-6 carbon atoms.
  • Cycloaliphatic groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, and cyclooctadienyl.
  • cycloaliphatic also include aliphatic rings that are fused to one or more aromatic or nonaromatic rings, such as decahydronaphthyl, tetrahydronaphthyl, decalin, or bicyclo[2.2.2]octane. These aliphatic rings can be optionally substituted as described herein.
  • cycloalkyl means a saturated cyclic aliphatic monocyclic or bicyclic ring system having from 3-18, for example 3-12 members.
  • a cycloalkyl can be optionally substituted as described herein.
  • a cycloalkyl has 3-6 carbons.
  • a cycloalkyl group can be optionally substituted as described herein.
  • heterocyclyl means a saturated or unsaturated aliphatic ring system having from 3 to 18, for example 3-12 members in which at least one carbon atom is replaced with a heteroatom selected from N, S and O.
  • a heterocyclyl can contain one or more rings, which may be attached together in a pendent manner or may be fused.
  • a heterocyclyl is a three- to seven-membered ring system and includes, for example, and without being limited thereto, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl and the like.
  • a heterocyclyl group can be optionally substituted as described herein.
  • heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon, and includes any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quatemized form of any basic nitrogen; and a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl).
  • alkoxy means -O-alkyl.
  • Alkoxy can include a straight-chained or branched alkyl.
  • alkoxy has from one to eight carbon atoms and includes, for example, and without being limited thereto, methoxy, ethoxy, propyloxy, isopropyloxy, t-butoxy and the like.
  • An alkoxy group can be optionally substituted as described herein.
  • halo or “halogen” as used herein means halogen and includes, for example, and without being limited thereto, fluoro, chloro, bromo, iodo and the like, in both radioactive and non-radioactive forms.
  • haloalkyl means an alkyl group that is substituted with one or more halogen atoms.
  • haloalkyl refers to a perhalogenated alkyl group.
  • haloalkyl refers to an alkyl group which is substituted with one or more halogen atoms.
  • Exemplary haloalkyl groups include -CF 3 , -CF 2 H, -CCI 3 , - CF 2 CH 3 , -CH 2 CF 3 , -CH 2 (CF 3)2, -CF 2 (CF 3 )2, and the like.
  • Preferred haloalkyl groups include -CF 3 and -CF 2 H.
  • a preferred haloalkyl group is -CF 3 .
  • alkylene means a bivalent branched or unbranched saturated hydrocarbon radical.
  • alkylene has one to six carbon atoms, and includes, for example, and without being limited thereto, methylene, ethylene, n-propylene, n-butylene and the like. An alkylene group can be optionally substituted as described herein.
  • alkenylene has two to six carbon atoms, and includes, for example, and without being limited thereto, ethenylene, n-propenylene, n-butenylene and the like.
  • An alkenylene group can be optionally substituted as described herein.
  • alkynylene means a bivalent branched or unbranched hydrocarbon radical having one or more carbon-carbon triple bonds (i.e., -CoC-).
  • alkynylene has two to six carbon atoms, and includes, for example, and without being limited thereto, ethynylene, n-propynylene, n-butynylene and the like.
  • An alkynylene group can be optionally substituted as described herein.
  • aryl alone or in combination, as used herein, means a carbocyclic aromatic system containing one or more rings, which may be attached together in a pendent manner or may be fused. In some embodiments, an aryl has one, two or three rings. In one aspect, the aryl has six to twelve ring atoms.
  • aryl encompasses aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl and acenaphthyl.
  • An “aryl” group can have 1 to 4 substituents, such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, lower alkylamino and the like.
  • heteroaryl alone or in combination, as used herein, means an aromatic system wherein at least one carbon atom is replaced by a heteroatom selected from N, S and O.
  • a heteroaryl can contain one or more rings, which may be attached together in a pendent manner or may be fused.
  • a heteroaryl has one, two or three rings.
  • the heteroaryl has five to twelve ring atoms.
  • heteroaryl encompasses heteroaromatic groups such as triazolyl, imidazolyl, pyrrolyl, pyrazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, furyl, benzofuryl, thienyl, benzothienyl, quinolyl, oxazolyl, oxadiazolyl, isoxazolyl, and the like.
  • a “heteroaryl” group can have 1 to 4 substituents, such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, lower alkylamino and the like.
  • substituents and substitution patterns on the compounds of the invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below.
  • substituted whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • an “optionally substituted group” can have a suitable substituent at each substitutable position of the group and, when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position.
  • an “optionally substituted group” can be unsubstituted.
  • Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. If a substituent is itself substituted with more than one group, it is understood that these multiple groups can be on the same carbon atom or on different carbon atoms, as long as a stable structure results.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • Suitable monovalent substituents on R° are independently halogen, -(CH 2 ) 0-2 R ⁇ , -(haloR ⁇ ), -(CH 2 ) 0-2 OH, -(CH 2 ) 0-2 OR ⁇ , -(CH 2 )o- 2 CH(OR ⁇ ) 2 ; -O(haloR ⁇ ), -CN, -Ns, -(CH 2 ) 0-2 C(O)R ⁇ , -(CH 2 ) 0-2 C(O)OH, -(CH 2 )o- 2 C(O)OR ⁇ , -(CH 2 ) 0-2 SR ⁇ , -(CH 2 ) 0-2 SH, -(CH 2 ) 0-2 NH 2 , -(CH 2 ) 0-2 NHR ⁇ , -(CH 2 )
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -0(CR * 2) 2-3 O-, wherein each independent occurrence of R * is selected from hydrogen, C 1 - 6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Suitable substituents on the aliphatic group of R * include halogen, - R ⁇ , -(haloR ⁇ ), -OH, -OR ⁇ , -O(haloR ⁇ ), -CN, -C(O)OH, -C(O)OR ⁇ , -NH 2 , NHR*, -NR ⁇ 2, and -NO 2 , wherein each R ⁇ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1-4 aliphatic, -CH 2 Ph , -0(CH 2 ) 0-1 Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Suitable substituents on a substitutable nitrogen of an “optionally substituted group” include -R ⁇ , -NR ⁇ 2 , -C(O)R ⁇ , -C(O)OR ⁇ , -C(O)C(O)R ⁇ , -C(O)CH 2 C(O)R ⁇ , - S(O) 2 R ⁇ , -S(O) 2 NR ⁇ 2, -C(S)NR ⁇ 2, -C(NH)NR ⁇ 2, and -N(R ⁇ )S(O) 2 R ⁇ ; wherein each R ⁇ is independently hydrogen, C 1 - 6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or, notwithstanding the definition above, two independent occurrences
  • Suitable substituents on the aliphatic group of R ⁇ are independently halogen, - R ⁇ , -(haloR ⁇ ), -OH, -OR ⁇ , -O(haloR ⁇ ), -CN, -C(O)OH, -C(O)OR ⁇ , -NH 2 , -NHR ⁇ , -NR ⁇ 2, or -NO 2 , wherein each R ⁇ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1-4 aliphatic, -CH 2 Ph , -0(CH 2 ) 0-1 Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Example embodiments of compounds of structural formula (I) are selinexor, eltanexor, and vedinexor.
  • Eltanexor is a compound represented by the following structural formula, pharmaceutically acceptable salt thereof.
  • XPOl inhibitor selinexor is represented by the following structural formula, pharmaceutically acceptable salt thereof.
  • Verdinexor represented by structural formula (3), is an oral inhibitor or XPOl also described in WO 2 013/019548. pharmaceutically acceptable salt thereof.
  • the 3 canonical members of the Ras gene family were identified more than a quarter century ago because of their frequent oncogenic activation in human tumors. They are the founding members of the wider Ras superfamily including more than 150 small GTPases, divided into at least 5 distinct subfamilies (Ras, Rho/Rac, Rab, Arf, and Ran) on the basis of primary sequence relationships.
  • the Ras subfamily encompasses the hRas, nRas, and kRas genes together with the closely related rRas/TC21, Ral, and Rap loci.
  • Ras superfamily proteins share very similar molecular structures and a common ability to bind and hydrolyze guanine nucleotides.
  • the Ras proteins are continually cycling between active (GTP bound) and inactive (GDP bound) conformational states dependent on structural changes occurring mostly in the 2 motile switch I and switch II regions, which are also responsible for the functional interactions of these proteins with negative (GAP) and positive (GEF) cellular regulators.
  • GAP negative
  • GEF positive
  • the binary behavior aspects of these proteins enable them to function as molecular switches in a broad range of signaling processes related to the transduction of extracellular signals to the interior of cells.
  • Oncogenic mutations at positions 12, 13, or 61 of the HRAS , NRAS and KRAS genes are among the most common genetic lesions in mammalian tumors. These mutations result in significant impairment of the overall GTPase activity of the carrier RAS proteins and lock them into a constitutively activated state in which they signal to downstream effectors, even in the absence of extracellular stimul
  • NRAS, KRAS and HRAS are three separate human genes. Activating mutations within any one of these genes result in constitutively active gene products implinated in various malignancies. The frequencies of the different activating mutations in the different genes are variable across cancer types - HRAS mutations are less commonly mutated compared to KRAS and NRAS across human cancers, and HRAS mutations are rare in multiple myeloma (MM).
  • the kRas, nRas, and hRas gene products refer to, but is not limited to, the following.
  • KRAS can also refer to human Isoform 2B (SEQ ID NO: 2).
  • the sequence of this isoform differs from the canonical sequence as follows:
  • HRAS can also refer to human Isoform 2 differs from the canonical sequence as follows:
  • DNA or RNA from cells of the patient’s (subject’s) tumor are assessed to determine RAS (e.g., NRAS, KRAS or HRAS) mutation status to identify patients who are likely to benefit from the methods described herein.
  • RAS e.g., NRAS, KRAS or HRAS
  • Mutation status is determined using standard sequencing methods known to those skilled in the art including, for example, Sanger sequencing, next generation sequencing (NGS, also called massive parallel sequencing.).
  • the tumor mutation is determined by a diagnostic assay selected from FoundationOne ® CDx, OncomineTMDx Target Test, Guardant360 ® CDx.
  • RAS e.g., NRAS, KRAS or HRAS
  • RAS e.g., NRAS, KRAS or HRAS
  • Additional details relating to sequencing methods suitable for use can be found at the following url: https ://www. illumina. com/ content/ dam/illumina- marketing/documents/products/research reviews/sequencing-methods-review.pdf
  • RAS nucleotide encompasses the RAS genes, RAS mRNAs, RAS cDNAs and amplification products, mutations, variations and fragments thereof.
  • RAS refers to hRAS, kRAS and nRAS
  • RAS gene refers to the HRAS gene
  • KRAS gene and the NRAS gene or RAS protein refers to the HRAS, KRAS and NRas protein
  • RAS Protein refers to the polypeptide sequence that is produced by the translation of the RAS nucleotide or a portion thereof.
  • RAS mutation refers to alterations to a wild-type or parent RAS gene (i.e., the HRAS ,
  • alterations can be in the parent polynucleotide sequence encoding RAS, alterations to the parent polypeptide sequence of RAS, alterations to the parent polynucleotide sequence involved in RAS expression, multiplication or amplification in the number of RAS genes, multiplication or amplification in the number of RAS genes having one or more polynucleotide sequence mutations, or the like.
  • polynucleotide sequence mutations include missense mutations, nonsense mutations, splice site mutations, silent mutations, insertion mutations, nonsense mutations, splice site mutations, silent mutations, insertion mutations, deletion mutations, substitution mutations, promoter mutations, partial or whole gene duplication (or amplification) mutations, frameshift mutations, repeat expansion mutations, inversion mutations and translocation mutations.
  • a sequence mutation can affect a single nucleotide (point mutations) a few nucleotides, tens of nucleotides, the entire gene sequence or a chromosomal segment.
  • a G12C KRAS mutation refers to point mutation(s) of the basepairs comprising codon 12 of KRAS that causes the glycine of the wild-type KRAS protein to be substituted by a cysteine.
  • a RAS mutated cancer cell can comprise one or more RAS mutations.
  • a plurality of RAS- mutated cancer cells in a subject can be composed of populations of cells that each comprise the same RAS mutation or a population of cells having heterogeneous RAS mutation.
  • Mutations in a RAS gene, such as an NRAS, KRAS or HRAS that cause increased activity of the RAS protein or increased expression of encoded product (e.g., polypeptide/protein product) are known as “activating mutations.” For example, an activating mutation increases expression of a protein product which can result in inappropriate expression of the protein product or can result in increased or inappropriate activity of the protein product.
  • Such mutations can be constitutive (i.e., always causing increased activity) or transient (e.g., pulsed for a limited duration or inducible).
  • An activating mutation can result from a constitutively acting protein product, gain in copy number (e.g., amplification mutation), inappropriate expression of the gene due to mutation of or switching of expression control elements (e.g., promoter).
  • a mutation is a mutation in any one of codons 12, 13, or 61 of any one of KRAS, NRAS or HRAS.
  • the mutation is an activating mutation.
  • a mutation is any one or more of the following mutations resulting from an amino acid substitution in the protein expressed by the wild-type gene a) in nRas: Q61I, Q61K, Q61L, Q61H, Q61R, G12D, G12R, G12S, G13R,
  • the mutation is an activating mutation.
  • the one or more RAS mutations can be an amino acid substitution of the protein product of the RAS gene at position G12, G13, G60, Q61, LI 9, Y64 or any combination thereof.
  • the one or more RAS mutations can be an NRAS mutation (e.g., an activating mutation) having one or more of the following amino acid substitutions: Q61I, Q61K, Q61L, Q61H, Q61R, G12D, G12R, G12S, G13R, A83G, D54Y, D57A, M72I, E62K, G12A, G12V, G13K in SEQ ID NOS: 3 or 4 described herein.
  • the at least one NRAS mutation e.g.
  • the RAS activating mutation is one or more of the following amino acid substitutions: Q61K, Q61L, Q61H, Q61R, G13R, G12A, G12V of SEQ ID NOS: 3 or 4.
  • the RAS activating mutation can be one or more kRAS mutations (e.g., an activating mutation) having one or more of the following amino acid substitutions: Q61H, Q61R, Q61K, Q61E, G12H, G12A, G12R, G12S, G12V, G12C, G12D, G13D, G13C, G13V, A59T, A59G, A146T, K117N, L19F, E63K, Q22K, K88*, R123*, E3K, G60R, G60D, V7*, G12M, Y64N of SEQ ID NOS: 1 or 2 described herein.
  • the one or more KRAS mutations is one or more of the following amino acid substitutions: Q61H, Q61R, G12A, G12V, G12C, G12D, G13D, G13V, L19F, G60R, G60D, V7*, G12M, Y64N of SEQ ID NOS: 1 or 2.
  • the sample is a nucleic acid sample.
  • the nucleic acid sample comprises DNA or RNA, e.g., genomic DNA or cDNA or RNA e.g., mRNA.
  • the sample is a protein sample.
  • nucleic acid hybridization assays e.g., in situ hybridization, comparative genomic hybridization, microarray, Southern blot, northern blot
  • amplification-based assays e.g., PCR, PCR-RFLP assay or real-time PCR
  • sequencing and genotyping e.g., sequence-specific primers, high-performance liquid chromatography or mass spectrometric genotyping
  • screening analysis including metaphase cytogenetic analysis by karyotype methods
  • the RAS mutation is detected in a RAS protein.
  • the method comprises the steps of obtaining a patient sample (e.g., a tumor sample) and exposing the sample to at least on reagent that detects RAS protein containing a mutation (e.g., an antibody that recognizes the mutated RAS protein, but does not recognize the wild-type RAS protein) to determine whether the mutation RAS protein is present in the sample.
  • the mutant RAS protein can be detected in a patient sample by a method selected from any one of: antibody-based detection (e.g., western blot, ELISA, immunohistochemistry), size based detection methods (e.g., HPLC or mass spectrometry), or protein sequencing.
  • subject to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs; and/or birds, including commercially relevant birds such as chickens, ducks, geese, quail, and/or turkeys. In particular, subjects are humans, such as adult humans.
  • a pediatric subject e.g., infant, child, adolescent
  • adult subject e.g., young adult, middle-aged adult or senior adult
  • other primates e.g., cynomolgus monkeys, rhes
  • the subject is an adult human.
  • the adult human subject is suffering from multiple myeloma.
  • the adult human subject has received at least one prior therapy to treat the multiple myeloma.
  • the subject is an adult human suffering from relapsed or refractory multiple myeloma.
  • the adult human suffering from relapsed or refractory multiple myeloma has received at least four prior therapies.
  • the adult human subject is suffering from relapsed or refractory multiple myeloma has received at least four prior therapies for multiple myeloma and the multiple myeloma is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody.
  • treating means to decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease (e.g., a disease or disorder delineated herein), lessen the severity of the disease or improve the symptoms associated with the disease.
  • Treatment includes treating a symptom of a disease, disorder or condition.
  • combination therapy embraces the administration of the XPOl inhibitors of the present invention and one or more additional therapeutic agents as part of a specific treatment regimen intended to provide a beneficial effect from the co-action of each.
  • combination therapy includes the administration of one additional therapeutic agent, two additional therapeutic agents, three additional therapeutic agents, four additional therapeutic agents, five additional therapeutic agents etc.
  • the XPOl inhibitors of the present invention and the one or more additional therapeutic agents can be formulated as separate compositions. Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually minutes, hours, days or weeks depending upon the combination selected).
  • Combination therapy or “co-administration” is intended to embrace administration of the XPOl inhibitors of the present invention and one or more additional therapeutic agent, (e.g., one additional therapeutic agent, two additional therapeutic agents, three additional therapeutic agents, four additional therapeutic agents, five additional therapeutic agents etc.) in a sequential manner, that is, wherein each therapeutic agent (e.g., the XPOl inhibitor described herein and the at least one additional therapeutic agent) is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner.
  • Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for each of the therapeutic agents.
  • Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, an injection route (e.g., intravenous, subcutaneous), intramuscular routes, and direct absorption through mucous membrane tissues.
  • the therapeutic agents can be administered by the same route or by different routes.
  • the XPOl inhibitor of the combination may be administered by orally while the at least one additional therapeutic agent of the combination (e.g., bortezomib) may be administered by injection (intravenous or subcutaneous) or vice versa.
  • all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection.
  • the sequence wherein the therapeutic agents are administered is not narrowly critical. “Combination therapy” also can embrace the administration of the therapeutic agents as described above in further combination with non-drug therapies (e.g., surgery or radiation).
  • additional therapeutic agents include agents other than XPOl Inhibitors.
  • the one or more additional therapeutic agents can be selected from a glucocorticoid or anti-cancer agents (e.g., anti-cancer agents typically used to treat multiple myeloma).
  • glucocorticoids include beclomethasone, betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone and triamcinolone.
  • the glucocorticoid is dexamethasone.
  • the at least one additional therapeutic agent e.g, one additional therapeutic agent, two additional therapeutic agents, three additional therapeutic agents, four additional therapeutic agents, five additional therapeutic agents etc.
  • Such anti-cancer agents include, but are not limited to, proteosome inhibitors (e.g., bortezomib, earfilzomib and ixazomib citrate), monoclonal antibodies (e.g., Darzalex (anti-CD38), elotuzumab, sarclisa (anti-CD38) and belantamab mafodotin), immunomodulatory imide drugs (IMiD) (e.g., lenalidomide and pomalidomide, thalidomide), alkylating agents (e.g.
  • proteosome inhibitors e.g., bortezomib, earfilzomib and ixazomib citrate
  • monoclonal antibodies e.g., Darzalex (anti-CD38), elotuzumab, sarclisa (anti-CD38) and belantamab mafodotin
  • IiD immunomodulatory im
  • combination treatment comprises the administration of the XPOl inhibitors of the present invention (e.g., selinexor) in combination with dexamethasone.
  • the XPOl inhibitor e.g., selinexor at about 80 mg
  • the dose of selinexor can be adjusted to 100 mg once weekly, 80 mg once weekly or 60 mg once weekly as needed.
  • Dexamethasone administration is continued with each dose of selinexor.
  • combination treatment comprises the administration of the XPOl inhibitors of the present invention (e.g., selinexor) in combination with one or more (e.g,, 1, 2 or 3) of the following additional therapeutic agents: lenalidomide, pomalidomide, earfilzomib, bortezomib or duratumumab, and dexamethasone.
  • the XPOl inhibitor of the present invention e.g., selinexor
  • the XPOl inhibitor of the present invention is e.g., selinexor
  • the one or more additional therapeutics agents are two additional therapeutic agents being the combination of a glucocorticoid (e.g., dexamethasone) and a proteasome inhibitor (e.g., bortezomib).
  • a glucocorticoid e.g., dexamethasone
  • a proteasome inhibitor e.g., bortezomib
  • the XPOl inhibitor e.g., selinexor
  • the XPOl inhibitor is administered in the following regimens:
  • XPOl inhibitor e.g. selinexor
  • additional therapeutic agents a. Lenalidomide and methylprednisolone, prednisone or dexamethasone; b. Liposomal doxorubicin and dexamethasone; c. Carfilzomib and dexamethasone; d. Pomalidomide and dexamethasone; e. Daratumumab and dexamethasone; f. Melphalan and dexamethasone; g. Bortezomib and dexamethasone; h. Dexamethasone; i. Ixazomib and dexamethasone; j .
  • k Dexamethasone, pomalidomide and bortezomib
  • l Dexamethasone, pomalidomide and elotuzumab
  • m Dexamethasone and belantamab mafodotin
  • n Dexamethasone, pomalidomide and daratumumab
  • o Dexamethasone, pamalidomide and carfilzomib
  • p Dexamethasone, lenalidomide and bortezomib
  • q Dexamethasone, daratumumab and lenalidomide
  • the treatment comprises administering a combination of the XPOl inhibitors of the present invention (e.g., selinexor (also referred to herein as XPOVIO)), bortezomib and dexamethasone.
  • XPOl inhibitors of the present invention e.g., selinexor (also referred to herein as XPOVIO)
  • bortezomib e.g., bortezomib
  • dexamethasone e.g., the subject has not been previously treated with a proteasome inhibitor (PI naive).
  • PI naive proteasome inhibitor
  • selinexor is orally administered on Days 1, 8, 15, 22, and 29 of a 35-day cycle (e.g., at 100 mg per dose); bortezomib is subcutaneously administered on Days 1, 8, 15, and 22 of a 35-day cycle (e.g., at 1.3 mg/m2) and dexamethasone is orally administered on Days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 of each 35-day cycle at 20 mg per dose.
  • the length of the cycle can be adjusted accordingly, maintaining the once weekly administration for selinexor and bortezomib and the twice weekly administration of dexamethasone. If needed the dose of selinexor can be reduced to 80 mg once weekly, 60 mg once weekly or 40 mg once weekly.
  • the combined administration of the compound of XPOl inhibitor and one or more additional therapeutic agents can provide an enhanced therapeutic effect or can demonstrate synergy ( i.e . show a therapeutic effect that is greater than the additive effect resulting from separate administration of each component of the combination).
  • An advantage of a synergistic effect of the combination therapy is the ability to use less of each agent than is needed when each is administered alone. As such, undesirable side effects associated with the agents are reduced (partially or completely).
  • the presence of synergistic effects can be determined using suitable method for assessing drug interaction.
  • Suitable methods include, for example, the Sigmoid-Emax equation, the equation of Loewe additivity and the median-effect equation.
  • the corresponding graphs associated with the equations referred to above are the concentration-effect curve, isobologram curve and combination index curve, respectively.
  • Examples of enhanced therapeutic effects include the ability to use a less of one or a portion of or all agents administered in the combination therapy than is needed when each is used alone, a prolonged therapeutic window of one or both compounds of the combination therapy, reduced side effects following administration of the combination therapy, reduced resistance of the target disorder (e.g., multiple myeloma) to one or both compounds of the combination, sensitization of target cells to the action of one or both compounds of the combination therapy, an increase in progression free survival (PFS) as compared to use of the agents not in combination (e.g. and increased PFS for patients treated with selinexor, dexamethasone and bortezomib in combination versus dexamethasone and bortezomib together).
  • PFS progression free survival
  • Suitable doses of the XPOl inhibitor per administration include doses of about or greater than about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, or about 1000 mg.
  • a suitable dose of the XPOl inhibitor can be from about 50 mg to about 300 mg (such as 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg or 300 mg).
  • Doses can be administered one or more time per day (e.g. once per day, twice per day, three times per day etc.). Dosing regimens can range from one to three time per week (e.g., once per week, twice per week, three times per week etc.).
  • the one or more additional therapeutic agents can be administered at the typical dose used in practice or can be determined by one of skill in the medical art using known methods and medical judgment.
  • one or more of the additional therapeutics agents is glucocorticoid (e.g., dexamethasone), it can be administered from about 1 mg to about 100 mg per dose, such as from about 10 mg to about 50 mg per dose, such as 10 mg, 20 mg, 30 mg, 40 mg or 50 mg per dose.
  • the glucocorticoid e.g., dexamethasone
  • the one or more of addition the additional therapeutic agents is a proteasome inhibitor (e.g., bortezomib) and can be administered from about 100 mg/m 2 to about 1 mg/m2, such as from about 40 mg/m2 to about 1 mg/m2 such as about 1.3 mg/m 2 .
  • a proteasome inhibitor e.g., bortezomib
  • the XPOl inhibitors of the present invention can be present in the form of pharmaceutically acceptable salt.
  • the salts of the XPOl inhibitors of the present invention refer to non-toxic “pharmaceutically acceptable salts.”
  • Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts.
  • Pharmaceutically acceptable acidic/anionic salts include acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl sulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate/diphospate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulf
  • the XPOl inhibitors of the present invention can be administered orally, nasally, ocularly, transdermally, topically, intravenously (both bolus and infusion), and via injection (intraperitoneally, subcutaneously, intramuscularly, intratumorally, or parenterally) either as alone or as part of a pharmaceutical composition comprising the XPOl inhibitors of the present invention and a pharmaceutically acceptable excipient.
  • the composition may be in a dosage unit such as a tablet, pill, capsule, powder, granule, liposome, ion exchange resin, sterile ocular solution, or ocular delivery device (such as a contact lens and the like facilitating immediate release, timed release, or sustained release), parenteral solution or suspension, metered aerosol or liquid spray, drop, ampoule, auto-injector device, or suppository.
  • a dosage unit such as a tablet, pill, capsule, powder, granule, liposome, ion exchange resin, sterile ocular solution, or ocular delivery device (such as a contact lens and the like facilitating immediate release, timed release, or sustained release), parenteral solution or suspension, metered aerosol or liquid spray, drop, ampoule, auto-injector device, or suppository.
  • compositions of the invention suitable for oral administration include solid forms such as pills, tablets, caplets, capsules (each including immediate release, timed release, and sustained release formulations), granules and powders; and, liquid forms such as solutions, syrups, elixirs, emulsions, and suspensions.
  • “prior therapies” refers to known therapies for multiple myeloma involving administration of a therapeutic agent.
  • Prior therapies can include, but are not limited to, treatment with proteasome inhibitors (PI), Immunomodulatory agents, anti-CD38 monoclonal antibodies or other agents typically used in the treatment of multiple myeloma such as glucocorticoids.
  • Specific prior therapies can include bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, glucocorticoids or an alkylating agent [00167]
  • the present invention is a method of treating multiple myeloma (MM) in a subject in need thereof, comprising the steps of: obtaining a sample from the subject; determining the presence or absence of one or more RAS mutations in the sample; and administering a therapeutically effective amount of a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof:
  • Ring A is phenyl or pyridyl
  • X is -N- or -C(H)-;
  • each R 1 is independently selected from -CN, halo, - OH, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 3-18 membered heterocycloalkyl, halo-C 1 -C 4 alkyl, -NH 2 , -NO 2 , -NH(C 1 -C 4 alkyl), -N(C 1 -C 3 alkyl)(C 1 -C 3 alkyl), -C(O)OH, -C(O)O-(C 1 -C 6 alkyl), -C(O)-(C 1 -C 4 alkyl), -O-(C 1 -C 4 alkyl), -O-(C 1 -C 4 haloalkyl), and -S-( C 1 -C 4 alkyl);
  • R 2 is selected from -C(O)-O-R 3 , -C(O)-N(R 5 )(R 6 ), -C(O)-N(R 7 )-N(R 5 )(R 6 ), [00175] -CN, -CF 3 , -S(O)I-2(C 1 -C 4 alkyl), 5-18 membered heteroaryl, and C 6 -C 18 aryl; [00176] R a is hydrogen and R b is selected from hydrogen, -C(O)-O-R 3’ , -C(O)-N(R 5’ )(R 6’ ), -C(O)-N(R r )-N(R 5’ )(R 6’ ), -CN, -C(S)-O-R 3’ , -C( S)-N(R 5 )(R 6 ), -C(S)-N(R 7’ )-N(R 5 )
  • R 5 , R 5 , R 6 and R 6 are each independently selected from hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 18 carbocyclyl, C 6 -C 18 aryl, 3-18-membered heterocyclyl and 5-18-membered heteroaryl; or
  • R 5 and R 6 or R 5 and R 6 are each independently taken together with the nitrogen atom to which they are commonly attached to form a 3-18-membered heterocyclyl or 5-18- membered heteroaryl;
  • each R 7 and R 7’ are each independently hydrogen or C 1 -C 4 alkyl; and [00181] n is 0, 1, 2, 3, 4 or 5;
  • each alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, aryl, cycloalkyl, heterocyclyl and heteroaryl is optionally and independently substituted.
  • the present invention is a method of treating multiple myeloma in a subject in need thereof, the method comprising: administering a therapeutically effective amount of a compound represented by structural formula (I)
  • the present invention is a method of selecting and treating a subject suffering from multiple myeloma (MM), comprising the steps of: selecting the subject only if the subject has been determined to have one or more RAS mutations; and administering to the selected subject a therapeutically effective amount of a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof,
  • the present invention is a method of treating multiple myeloma in a subject in need thereof, comprising the steps of: receiving information about the absence or presence of one or more RAS mutations in the subject; and administering a therapeutically effective amount of a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof
  • R 5 and R 6 are each independently selected from hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 18 carbocyclyl, C 6 -C 18 aryl, 3-18-membered heterocyclyl and 5- 18-membered heteroaryl; or
  • the additional therapeutic agent is selected from a glucocorticoid, a proteosome inhibitor, an anti-CD38 monoclonal antibody, an immunomodulatory imide drug (IMiD), an alkylating agent, a topoisomerase 2 inhibitor and an HD AC inhibitor.
  • IiD immunomodulatory imide drug
  • the additional therapeutic agent is selected from a glucocorticoid and a proteasome inhibitor.
  • the RAS mutation comprises one or more mutations of kRAS, one or more mutations of nRAS or a combination thereof.
  • the remainder of the features, values and example values are as defined above with respect to the 1 st through 6 th aspects of any of the example embodiments.
  • the RAS mutation comprises a point mutation at one of more of codons 12, 13 or 61 of kRAS, nRAS or a combination thereof.
  • the one or more RAS mutation is a kRAS mutation comprising an amino acid substitution at one or more of the following positions of the kRAS polypeptide of SEQ ID NO. 1 or SEQ ID NO. 2: Q61H, G12C,
  • the one or more RAS mutation is a nRAS mutation comprising an amino acid substitution at one or more of the following positions of the nRAS polypeptide of SEQ ID NO. 3: G12A, Q61H, Q61K, Q61L, Q61R, G12V and G13R.
  • the multiple myeloma is a relapsed or refractory multiple myeloma.
  • the subject has received from 1 to 7 prior therapies.
  • the remainder of the features, values and example values are as defined above with respect to the 1 st through 11 th aspects of any of the example embodiments.
  • the subject has received at least one prior therapy.
  • the subject is a human, for example an adult human.
  • the compound of structural formula (I) or a pharmaceutically acceptable salt thereof is administered orally.
  • the compound of structural formula (I) or a pharmaceutically acceptable salt thereof is orally administered using a dosing regimen comprising multiple weeks of treatment and 100 mg/per day is administered on day 1 of each week of treatment.
  • two additional therapeutics agents are administered and are dexamethasone and bortezomib.
  • the dexamethasone is orally administered at an amount of 20 mg/day on days 1 and 2 of each week of treatment.
  • bortezomib is administered at 1.3 mg/m 2 on day 1 of each week of treatment.
  • Example 1 Effects of weekly selinexor. bortezomib. dexamethasone (XVd) versus stand twice weekly bortezomib and dexamethasone (Vd) on RAS-mutated previously treated multiple myeloma (MM)
  • BOSTON The efficacy of XPOVIO in combination with bortezomib and dexamethasone (XVd) was evaluated in BOSTON (NCT03110562).
  • BOSTON was a global, randomized, open label, active-controlled trial in adult patients who had received 1 to 3 prior anti-Multiple Myeloma (MM) regimens.
  • Prior treatment with bortezomib or other Proteosome Inhibitors (PI) was allowed.
  • Bortezomib 1.3 mg/m 2 administered subcutaneously twice weekly on Days 1, 4, 8, 11 and dexamethasone 20 mg taken orally four times weekly on Days 1, 2, 4, 5, 8, 9, 11, 12 of each 21-day cycle for the first 8 cycles, followed by bortezomib 1.3 mg/m2 administered subcutaneously once weekly on Days 1, 8, 15, 22 and dexamethasone 20 mg taken orally twice weekly on Days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 of each 35-day cycle (Cycle >9) [Vd arm],
  • Efficacy was based on progression free survival (PFS) according to the International Myeloma Working Group (IMWG) Uniform Response Criteria for Multiple Myeloma, as assessed by an Independent Review Committee (IRC).
  • PFS progression free survival
  • IRC Independent Review Committee
  • XPOVIO in combination with bortezomib and dexamethasone (XVd) is indicated for the treatment of adult patients with multiple myeloma who have received at least one prior therapy.
  • the recommended dosage of XPOVIO is 100 mg taken orally once weekly on Day 1 of each week until disease progression or unacceptable toxicity in combination with: Bortezomib 1.3 mg/m 2 administered subcutaneously once weekly on Day 1 of each week for 4 weeks followed by 1 week off; and dexamethasone 20 mg taken orally twice weekly on Days 1 and 2 of each week.
  • STORM The efficacy of XPOVIO plus dexamethasone (Sd or Xd) was evaluated in STORM (NCT02336815). STORM was a multicenter, single-arm, open-label study of adults with relapsed or refractory multiple myeloma (RRMM).
  • STORM Part 2 included 122 patients with RRMM who had previously received three or more anti-myeloma treatment regimens including an alkylating agent, glucocorticoids, bortezomib, carfilzomib, lenalidomide, pomalidomide, and an anti-CD38 monoclonal antibody; and whose myeloma was documented to be refractory to glucocorticoids, a proteasome inhibitor, an immunomodulatory agent, an anti-CD38 monoclonal antibody, and to the last line of therapy.
  • STORM Part 2 a total of 122 patients received XPOVIO 80 mg orally in combination with dexamethasone 20 mg orally on Days 1 and 3 of every week (. Treatment continued until disease progression or unacceptable toxicity. Eighty -three patients had RRMM that was refractory to bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab.
  • Efficacy was based on overall response rate (ORR), as assessed by an Independent Review Committee (IRC) based on the International Myeloma Working Group (IMWG) Uniform Response Criteria for Multiple Myeloma.
  • ORR overall response rate
  • IRC Independent Review Committee
  • IMWG International Myeloma Working Group
  • the approval of XPOVIO was based upon the efficacy and safety in a prespecified subgroup analysis of the 83 patients whose disease was refractory to bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab, as the benefit-risk ratio appeared to be greater in this more heavily pretreated population than in the overall trial population.
  • XPOVIO in combination with dexamethasone is indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody.
  • the recommended dosage of XPOVIO is 80 mg taken orally on Days 1 and 3 of each week until disease progression or unacceptable toxicity in combination with dexamethasone 20 mg taken orally with each dose of XPOVIO on Days 1 and 3 of each week.
  • FIG. 2A through FIG. 2D which demonstrate that a combination of selinexor, bortezomib, and dexamethasone improves the chances of survival of RAS mut MM patients as compared to RAS wild-type .

Abstract

L'invention concerne un procédé de traitement du myélome multiple (MM) chez un sujet qui en a besoin, comprenant les étapes consistant à : obtenir un échantillon du sujet ; déterminer la présence ou l'absence d'une ou plusieurs mutations RAS dans l'échantillon ; et administrer une quantité thérapeutiquement efficace d'un composé représenté par la formule structurelle (I) ou d'un sel pharmaceutiquement acceptable de celui-ci ; et un ou plusieurs agents thérapeutiques supplémentaires au sujet sur lequel la présence d'une ou plusieurs mutations RAS a été déterminée. Des exemples de valeurs des variables dans la formule structurale (I) sont définis ici.
PCT/US2022/026766 2021-04-28 2022-04-28 Biomarqueurs pour la réponse à des inhibiteurs de l'exportine 1 chez des patients atteints d'un myélome multiple WO2022232417A1 (fr)

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WO2013019548A1 (fr) 2011-07-29 2013-02-07 Karyopharm Therapeutics, Inc. Modulateurs de transport nucléaire contenant de l'hydrazide et leurs utilisations
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WO2014004479A2 (fr) 2012-06-25 2014-01-03 Massachusetts Institute Of Technology Film poreux
WO2020092965A1 (fr) * 2018-11-01 2020-05-07 Karyopharm Therapeutics Inc. E2f1 en tant que biomarqueur pour des traitements utilisant des inhibiteurs de xpo1
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