T315A AND F317I MUTATIONS OF BCR-ABL KINASE DOMAIN
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IPC분류정보
국가/구분
United States(US) Patent
공개
국제특허분류(IPC7판)
A61K-031/497
C12Q-001/48
G01N-033/53
C12Q-001/68
출원번호
US-0092360
(2006-11-03)
공개번호
US-0029676
(2010-02-04)
국제출원번호
PCT/US2006/043019
(2006-11-03)
발명자
/ 주소
Sawyers, Charles L.
Burgess, Michael
Shah, Neil Pravin
Lee, Francis Y.
Tokarski, John S.
Klei, Herbert E.
대리인 / 주소
BRISTOL - MYERS SQUIBB COMPANY
인용정보
피인용 횟수 :
0인용 특허 :
0
초록
The present invention relates to mutant BCR-ABL kinase proteins, and to diagnostic and therapeutic methods and compositions useful in the management of disorders, for example cancers, involving cells that express such mutant BCR-ABL kinase proteins.
대표청구항▼
1. A method for determining the responsiveness of an individual with a BCR-ABL associated disorder to treatment with N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide, or a pharmaceutically acceptable salt, solvate, or hydrate t
1. A method for determining the responsiveness of an individual with a BCR-ABL associated disorder to treatment with N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, comprising: screening a biological sample from said individual for the presence of at least one mutation in a BCR-ABL polypeptide sequence; wherein the at least one mutation is a F317I mutation or a T315S mutation; and wherein the presence of the at least one mutation is indicative of the individual being at least partially resistant to N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide or a pharmaceutically acceptable salt, solvate, or hydrate thereof, therapy. 2. The method of claim 1 wherein the at least one mutation is a F317I mutation. 3. The method of claim 2 wherein the sample is further screened for the presence of a T315A mutation. 4. The method of claim 1 wherein the at least one mutation is a T315A mutation. 5. The method of claim 1 wherein the individual has not previously been treated with a kinase inhibitor. 6. The method of claim 1 wherein the individual has been previously treated with a kinase inhibitor and has developed at least partial resistance to the kinase inhibitor. 7. The method of claim 6 wherein the kinase inhibitor is N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide or a pharmaceutically acceptable salt, solvate, or hydrate thereof. 8. The method of claim 6 wherein the kinase inhibitor is imatinib, AMN107, PD180970, CGP76030, AP23464, SKI 606, or AZD0530. 10. The method of claim 9 wherein the leukemia is chronic myeloid leukemia (CML), Ph+ ALL, AML, imatinib-resistant CML, imatinib-intolerant CML, accelerated CML, or lymphoid blast phase CML. 11. The method of claim 1 wherein the sample is further screened for the presence of a E279K, F359C, F3591, L3641, L387M, F486S, D233H, T243S, M244V, G249D, G250E, G251S, Q252H, Y253F, Y253H, E255K, E255V, V256L, Y257F, Y257R, F259S, K262E, D263G, K264R, S265R, V268A, V270A, T272A, Y274C, Y274R, D276N, T277P, M278K, E279K, E282G, F283S, A288T, A288V, M290T, K291R, E292G, 1293T, P296S, L298M, L298P, V299L, Q300R, G303E, V304A, V304D, C305S, C305Y, T306A, F311L, I314V, T315I, E316G, F317L, M318T, Y320C, Y320H, G321E, D325H, Y326C, L327P, R328K, E329V, Q333L, A337V, V339G, L342E, M343V, M343T, A344T, A344V, I347V, A350T, M351T, E352A, E352K, E355G, K357E, N358D, N358S, F359V, F359C, F359I, I360K, I360T, L364H, L3641, E373K, N374D, K378R, V379I, A380T, A380V, D381G, F382L, L387M, M388L, T389S, T392A, T394A, A395G, H396K, H396R, A399G, P402T, T406A, S417Y, F486S or any combination thereof, mutation. 12. The method of claim 3 wherein the sample is further screened for the presence of a M244V, G250E, Q252H, Q252R, Y253F, Y253H, E255K, E255V, T315I, F317L, M351T, E355G, F359V, H396R, F486S, or any combination thereof, mutation. 13. The method of claim 3 wherein the sample is further screened for the presence of a M244V, E279K, F359C, F359I, L364I, L387M, or F486S, or any combination thereof, mutation. 14. The method of claim 3 wherein the sample is further screened for the presence of a L248R, Q252H, E255K, V299L, T315I, F317V, F317L, F317S, or any combination thereof, mutation. 15. A method of treating an individual suffering from a BCR-ABL-associated disorder comprising: mutation or a T315A mutation, wherein the presence of the at least one mutation is indicative of the patient being at least partially resistant to N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, therapy; and administering a therapeutically effective amount of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, to the individual. 16. The method of claim 15 wherein the thiazolecarboxamide, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered at a higher dosage or dosing frequency if it is determined that the biological sample comprises a BCR-ABL polypeptide having the at least one mutation. 17. The method of claim 16, wherein the biological sample comprises a BCR-ABL polypeptide having the at least one mutation and the thiazolecarboxamide or pharmaceutically acceptable salt, hydrate, or solvate thereof is administered at a dosage of greater than 70 mg twice daily. 18. The method of claim 15 wherein the thiazolecarboxamide, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered in combination with a second therapy to treat the protein tyrosine kinase associated disorder in the individual. 19. The method of claim 18 wherein the second therapy is a tubulin stabilizing agent, a farnysyl transferase inhibitor, a BCR-ABL T315I inhibitor, a second protein tyrosine kinase inhibitor, or a combination thereof. 20. The method of claim 16 wherein the thiazolecarboxamide, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered in combination with a second therapy to treat the protein tyrosine kinase associated disorder in the individual. inhibitor, or a combination thereof. 22. A method of identifying a compound that specifically binds to a BCR-ABL polypeptide, wherein the BCR-ABL polypeptide comprises at least one of a F317I mutation or a T315A mutation, comprising: contacting a test compound with the BCR-ABL polypeptide; and determining whether the BCR-ABL polypeptide specifically binds to the test compound. 23. The method of claim 22 further comprising a step of determining whether the test compound modulates the tyrosine kinase activity of the BCR-ABL polypeptide. 24. The method of claim 23 wherein the test compound inhibits the tyrosine kinase activity of the BCR-ABL polypeptide. 25. A method of determining whether a test compound modulates the tyrosine kinase activity of a BCR-ABL polypeptide, wherein the BCR-ABL polypeptide comprises at least one of a F317I mutation or a T315A mutation, comprising: obtaining mammalian cells transfected with a construct encoding the BCR-ABL polypeptide so that the BCR-ABL polypeptide is expressed by the mammalian cells; contacting the mammalian cells with the test compound; and monitoring the mammalian cells for tyrosine kinase activity of the BCR-ABL polypeptide wherein a modulation in tyrosine kinase activity in the presence of the test compound identifies the test compound as a modulator of the BCR-ABL polypeptide. 26. The method of claim 25 wherein the test compound inhibits the tyrosine kinase activity of a BCR-ABL polypeptide. 27. A kit for use in determining treatment strategy for an individual with a BCR-ABL-associated disorder, comprising a means for detecting a mutant BCR-ABL in a biological sample from said individual; and optionally instructions for use and interpretation of the kit results. 6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide, or a pharmaceutically acceptable salt, hydrate or solvate thereof. 29. The kit of claim 27 wherein said mutant BCR-ABL comprises a mutation at position 315 or 317. 30. The kit of claim 29 wherein said mutation at position 315 is selected from the group consisting of T315I and T315A. 31. The kit of claim 29 wherein said mutation at position 317 is selected from the group consisting of F317I, F317V, F317L, and F317S. 32. The kit of claim 29 further comprising a means for obtaining a biological sample from said individual. 33. A kit for use in treating an individual with a mutant BCR-ABL associated disorder, comprising: a means for detecting a mutation at amino acid position 315 of a BCR-ABL from a biological sample from said individual; a therapeutically effective amount of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide, or a pharmaceutically acceptable salt or hydrate or solvate thereof; and instructions for use of said kit. 34. The kit of claim 33 wherein said mutation at amino acid position 315 is selected from the group consisting of T315I and T315A. 35. A kit for use in treating an individual with a mutant BCR-ABL associated disorder, comprising: a means for detecting a mutation at amino acid position 317 of a BCR-ABL from a biological sample from said individual; pharmaceutically acceptable salt or hydrate or solvate thereof; and instructions for use of said kit. 36. The kit of claim 35 wherein said mutation at amino acid position 315 is selected from the group consisting of F317I, F317V, F317L, and F317S. 37. A method of identifying amino acid positions within the BCR-ABL polypeptide that may confer at least partial resistance to a BCR-ABL inhibitor when said amino acid positions are mutated, comprising the steps of: creating a co-crystal of the polypeptide with said BCR-ABL inhibitor; and identifying the amino acid positions of said polypeptide that either contact, bond, interface or interact with said BCR-ABL inhibitor or that stabilize the contacting, bonding, interfacing, or interacting amino acids. 38. The method according to claim 37 wherein said BCR-ABL inhibitor is N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. 39. The method according to claim 38 wherein said amino acid positions are selected from the group consisting of: 248, 299, 315, and 317. 40. The method according to claim 38 wherein said amino acid positions are selected from the group consisting of: 244, 248, 255, 290, 299, 313, 315, 316, 317, 318, 320, 321, and 380.
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