WO2005062795B1 - Compounds and methods for development of ret modulators - Google Patents

Compounds and methods for development of ret modulators

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Publication number
WO2005062795B1
WO2005062795B1 PCT/US2004/042470 US2004042470W WO2005062795B1 WO 2005062795 B1 WO2005062795 B1 WO 2005062795B1 US 2004042470 W US2004042470 W US 2004042470W WO 2005062795 B1 WO2005062795 B1 WO 2005062795B1
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WO
WIPO (PCT)
Prior art keywords
optionally substituted
ret
compound
substituted lower
heteroaralkyl
Prior art date
Application number
PCT/US2004/042470
Other languages
French (fr)
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WO2005062795A2 (en
WO2005062795A3 (en
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Publication date
Priority to CN2004800419081A priority Critical patent/CN1925855B/en
Priority to DK04814626.0T priority patent/DK1696920T3/en
Priority to EP20040814626 priority patent/EP1696920B8/en
Priority to SI200432217T priority patent/SI1696920T1/en
Application filed filed Critical
Priority to PL04814626T priority patent/PL1696920T3/en
Priority to CA2550361A priority patent/CA2550361C/en
Priority to AU2004308299A priority patent/AU2004308299B2/en
Priority to JP2006545481A priority patent/JP5138938B2/en
Priority to ES04814626.0T priority patent/ES2527118T3/en
Publication of WO2005062795A2 publication Critical patent/WO2005062795A2/en
Publication of WO2005062795A3 publication Critical patent/WO2005062795A3/en
Publication of WO2005062795B1 publication Critical patent/WO2005062795B1/en
Priority to HK07102386.1A priority patent/HK1094878A1/en
Priority to HRP20141228TT priority patent/HRP20141228T1/en
Priority to CY20151100049T priority patent/CY1118328T1/en

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Abstract

Compounds active on Ret are described, as well as methods of using such compounds. Also described are crystal structures of Ret surrogates that were determined using X-ray crystallography. The use of such Ret surrogate crystals and strucural information can, for example, be used for identifying molecular scaffolds and for developing ligands that bind to and modulate Ret and for identifying improved ligands based on known ligands.

Claims

AMENDED CLAIMS received by the International Bureau on 19 January 2006 (19.01.2006)
1. A compound having the chemical structure
Figure imgf000002_0001
wherein:
R2 is selected from the group consisting of -CH2-optionally substituted aryl, -CH2-optionally substituted heteroaryl, -C(O)-optionally substituted aryl, -C(O)-0ptionally substituted heteroaryl, -S-optionally substituted aryl, -S-optionally substituted heteroaryl. -S(O)2-optionally substituted aryl, and - S(O)2-optionally substituted heteroaryl; and
R4 is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, -O-optionally substituted alkyl, -O-optionally substituted aryl, -O-optionally substituted heteroaryl, -NH-optionally substituted alkyl, -NH-optionally substituted aryl, and -NH-optionally substituted heteroaryl.
2. The compound of Claim 1, R4 is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, and optionally substituted heteroaryl.
3. The compound of claim 1, wherein said compound is a compound listed in Table 1.
4. A pharmaceutical composition comprising: a compound according to any of claims 1, 2 or 3; and a pharmaceutially acceptable carrier.
5. A method for treating a patient suffering from or at risk of a disease or condition for which Ret modulation provides a therapeutic benefit, comprising administering to said patient a Ret modulator having a chemical structure of a compound according to any of claims 1, 2 or 3.
6. The method of claim 5, wherein said compound is approved for administration to a human.
7. The method of claim 5, wherein said disease or condition is a Ret-mediated disease or condition.
537
8. The method of claim 5, wherein said disease or condition is selected from the group consisting of multiple endocrine neoplasia, type IIA (MEN2A), multiple endocrine neoplasia, type KB (MBN2B), Hirschsprung disease (HSCR; aganglionic megacolon), or medullary thyroid carcinoma (MTC), familial medullary thyroid carcinomas (FMTC), and papillary thyroid carcinomas (PTC).
9. A kit comprising a pharmaceutical composition comprising a compound according to any of claims 1, 2 or 3, or the pharmaceutical composition of claim 4.
10. The kit of claim, 9, further comprising a written indication that said composition is approved for administering to a human.
11. The kit of claim 10, wherein said composition is approved for a medical indication selected from the group consisting of multiple endocrine neoplasia, type IIA (MEN2A), multiple endocrine neoplasia, type 11B (MEN2B), Hirschsprung disease (HSCR; aganglionic megacolon), or medullary thyroid carcinoma (MTC)3 familial medullary thyroid carcinomas (FMTC)3 and papillary thyroid carcinomas (PTC).
12. A method for developing an improved modulator active on Ret, comprising; determining whether any of a plurality of test compounds of Formula I provides an improvement in one or more desired pharmacologic properties relative to a reference compound active on Ret; and selecting those compound(s) if any, that have an improvement in said desired pharmacologic property, thereby providing an improved modulator; wherein:
Formula I is
Figure imgf000003_0001
R1 and R5 are independently hydrogen, halo, hydroxy, optionally substituted alkoxyl, optionally substituted thioalkoxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyϊ, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralky]3 optionally substituted heteroaryl, optionally substituted heteroaralkyl, -C(X)NR16R17, -C(X)R20, or -NR22R23;
R2, R3, and R4 are independently hydrogen, halo, hydroxy, optionally substituted alkoxyl, optionally substituted thioalkoxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted atyl, optionally substituted aralkyl, optionally substituted heteroaryl., or optionally substituted heteroaralkyl, -C(X)R20, -C(X)NR16R17, -S(O)2NR16R17, -NR22R23 , Or-S(O)nR21;
R16 and R17 are independently hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyL optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or R16 and R17 together form a 5-7 membered carbocyclic or heterocyclic ring;
R20 is hydroxy!, optionally substituted lower alkoxy, optionally substituted amine, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl., optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;
R21 is hydrogen, optionally substituted lower alkyl, optionally substituted amine, optionally substituted lower alkenyl. optionally substituted lower alkynyL optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl;
R22 and R23 are independently hydrogen, optionally substituted lower alkyl, optionally substituted lower alkerryl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -C(X)R20, -C(X)NR16R17, or -S(O)2R21;
R24 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; and n - 0, 1, or 2.
13. The method of claim 12, wherein said desired pharmacologic property is at least 10-fold greater activity on Ret than on PGFRl.
14. The method of claim 12, wherein said desired property is an IC 50 of less than 0.10
15. The method of claim 12, wherein said reference compound is a compound of Formula I.
16. The method of claim 12, wherein at least one derivative of said improved modulator is used as a test compound and said determining and selecting are repeated.
17. A method for developing ligands which bind to Ret, comprising: identifying as molecular scaffolds one or more compounds that bind to a binding site of Ret or a Ret surrogate; determining the orientation of at least one molecular scaffold in co-crystals with a Ret surrogate; and identifying chemical structures of said molecular scaffolds, that, when modified, alter the binding affinity or binding specificity or both between the molecular scaffold and Ret; and synthesizing a ligand wherein one or more of the chemical structures of the molecular scaffold is modified to provide a ligand that binds to Ret with altered binding affinity or binding specificity or both,
18. The method of claim 17, wherein said molecular scaffold is a weak binding compound,
19. The method of claim 17, wherein said molecular scaffold binds to a plurality of kinases.
20. The method of claim 17, wherein said molecular scaffold includes the core structure of Formula I wherein:
Formula I is
Figure imgf000006_0001
Formula I
R1 and R5 are independently hydrogen, halo, hydroxy, optionally substituted alkoxyl, optionally substituted tliioalkoxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -C(X)NR16R17,
Figure imgf000006_0002
R2, R3- and R4 are independently hydrogen, halo, hydroxy, optionally substituted alkoxyl, optionally substituted thioalkoxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted lieterocycloalkyl, optionally substituted ajyl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl, -C(X)R20, -C(X)NR16R17, -S(O)2NR16R17, -NR22R23 , or -S (O)nR21;
R1G and R17 are independently hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl. optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or R16 and R17 together form a 5-7 membered carbocyclic or heterocyclic ring;
R20 is hydroxy, optionally substituted lower alkoxy, optionally substituted amine, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;
R21 is hydrogen, optionally substituted lower alkyl, optionally substituted amine, optionally substituted lower alkenyl, optionally substituted lower alkynyl,, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroatyl, optionally substituted heteroaralkyl; R22 and R23 are independently hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaxalkyl, -C(X)R20, -C(X)NR16R17, or -S(O)2R21;
R24 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; and n = Q, 1, or 2.
21. A method for developing ligands specific for Ret, comprising: identifying a compound that binds to a plurality of tyrosine kinases; and determining whether a derivative of said compound has greater specificity for Ret than said compound.
22. The method of claim 21 , wherein said compound binds to Ret with an affinity at least 10-fold greater than for binding to any of said plurality of tyrosine kinases.
23. The method of claim 22, wherein said compound interacts with at least one conserved Ret active site residue.
24. The method of claim 21, wherein said compound binds weakly to said plurality of tyrosine kinases.
25. The method of claim 21, wherein said plurality of tyrosine kinases comprises Ret and FGFRl.
26. The method of claim 21, wherein said plurality of tyrosine kinases comprises Ret, FGFR1, FGFR2, FGFR3, and FGFR4.
27. The method of claim 21, wherein said compound includes the core structure of Formula I , wherein:
Formula I is
542
Figure imgf000008_0001
Formula I
R1 and Rs are independently hydrogen, halo, hydroxy, optionally substituted alkoxyl, optionally substituted thioalkoxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted atalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -C(X)NR16R17, -C(X)R20, or-NR22R23;
R2, R3, and R4 are independently hydrogen, halo, hydroxy, optionally substituted alkoxyl, optionally substituted thioalkoxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted avalkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl, -C(X)R20, -C(X)NR16R17, -S(O)2NR16R17, -NR22R23 , or -S(O)nR21;
R16 and R17 are independently hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloatkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or R16 and R17 together form a 5-7 menibered carbocyclic or heterocyclic ring;
R20 is hydroxyl, optionally substituted lower alkoxy, optionally substituted amine, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl , optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;
R21 is hydrogen, optionally substituted lower alkyl, optionally substituted amine, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl , optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl;
543 R22 and R23 are independently hydrogen, optionally substituted lower alkyl, optionally substituted lower atkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclσatkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarallcyl, -C(X)R20, -C(X)HR16R17, Or -S(O)2R21;
R24 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; and n = 0, 13 or 2.
28. A method for obtaining a crystal of Ret surrogate, comprising subjecting Ret surrogate protein at 5-20 mg/rnl to crystallization condition substantially equivalent to 10-20% PEG 3350, Q, IM Hepes pH 6.5, 0.2M (NH4)2SO4, 10% ethylene glycol at 4°C.
29. The method of claim 28, further comprising optimizing said crystallization condition.
30. The method of claim 28, wherein said Ret surrogate is derived from FGFRl and comprises the amino acid substitutions present in Ret surrogate 2.
31. A co-crystal of Ret surrogate and a Ret binding compound.
32. The co-crystal of claim 31, wherein said binding compound interacts with at least one conserved Ret active site residue.
33. The co-crystal of claim 31, wherein said binding compound is a compound of Formula I, wherein:
Formula I is
Figure imgf000009_0001
R1 and R5 are independently hydrogen, halo, hydroxy, optionally substituted alkoxyl, optionally substituted thioalkoxy, optionally substituted lower alkyl, optionally substituted
544 lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -C(X)NR16R17, -C(X)R20, or -NR22R23;
R2, R3, and R4 are independently hydrogen, halo, hydroxy, optionally substituted alkoxyl, optionally substituted tbioalfcoxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl, -C(X)R20, -C(X)NR16R17, -S(O)2NR16R17, -NR22R23 , or -S(O)nR21;
R16 and R17 are independently hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or R16 and R17 together form a 5-7 membered carbocyclic or heterocyclic ring;
R20 is hydroxy!, optionally substituted lower alkoxy, optionally substituted amine, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;
R21 is hydrogen, optionally substituted lower alkyl, optionally substituted amine, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl;
R22 and R23 are independently hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl. -C(X)R20, -C(X)NR16R17, or -S(O)2R21;
R24 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; and n = 0, 1, or 2.
545
34. The co-crystal of claim 31, wherein said co-crystal is suitable for use in an X-ray beam..
35. The co-crystal of claim 33, wherein said binding compound includes the core structure of the compound of Formula I.
36. A method for determining a structure of a kinase, comprising creating a homology model from an electronic representation of a Ret surrogate structure containing representations of atomic coordinates as in any of Tables 3, 4, and 5 .
37. The method of claim 36, wherein said creating comprises: identifying conserved amino acid residues between Ret and said kinase; transferring the atomic coordinates of a plurality of conserved amino acids in said Ret surrogate structure to the corresponding amino acids of said kinase to provide a rough structure of said kinase; and constructing structures representing the remainder of said kinase using electronic representations of the structures of the remaining amino acid residues in said kinase.
38. The method of claim 37, further comprising fitting said homology model to low resolution x-ray diffraction data from one or more crystals of said kinase.
39. The method of claim 37, wherein the coordinates of conserved residues shown in any of Tables 3, 4, and 5 are utilized.
40. An electronic representation of a co-crystal structure of Ret or Ret surrogate binding site with a binding compound, wherein said crystal structure includes representations of atomic coordinates corresponding to binding site atoms of said 'Ret or Ret surrogate.
41. The electronic representation of claim 40, wherein said binding compound is a compound of Formula I,
Wherein:
Formula I is
Figure imgf000011_0001
546 Formula I
R1 and S5 are independently hydrogen, halo, hydroxy, optionally substituted alkoxyl, optionally substituted thioalkoxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, Optionally substituted heterocycloalkyϊ, optionally substituted aryl, optionally substituted aralkyi, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -C(X)NR16R17, -C(X)R20, or -NR22R23;
R2, R3, and R4 are independently hydrogen, halo, hydroxy, optionally substituted alkoxyl, optionally substituted thioalkoxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl optionally substituted cycloalkyl, optionally substituted Iieterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl, -C(X)R20, -C(X)NR16R17, -S(O)2NR16R17, -NR22R23 , or -S(O)nR21;
R16 and R17 are independently hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or R16 and R17 together form a 5-7 ϊneiribered carbocyclic or heterocyclic ring;
R20 is hydroxy!, optionally substituted lower alkoxy, optionally substituted amine, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;
R21 is hydrogen, optionally substituted lower alkyl, optionally substituted amine, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl;
R22 and R23 are independently hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted atyl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -C(X)R20, -C(X)NR16R17, or -S(O)2R21;
547 R24 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; and n= 0, 1, or 2.
42. The electronic representation of claim 40, comprising a schematic representation.
43. The electronic representation of claim 40, wherein atomic coordinates for a Ret surrogate binding site comprising the ammo acid sequence of Ret are used.
44. The electronic representation of claim 40, wherein said Ret surrogate consists essentially of a kinase domain.
45. The electronic representation of claim 40, wherein said binding compound includes a core structure different from the core structure of Formula I according to claim 41,
46. The electronic representation of claim 40, comprising a binding site surface contour,
47. The electronic representation of claim 40, comprising representations of the binding character of a plurality of conserved amino acid residues.
48. A method for developing a biological agent, comprising: analyzing a Ret surrogate crystal structure; and identifying at least one sub-structure for forming a said biological agent,
49. The method of claim 48, wherein said substructure comprises a Ret epitope, and said method further comprises developing antibodies against said epitope.
50. The method of claim 48, wherein said sub-structure comprises a mutation site expected to provide altered Ret activity, and said method further comprises creating a mutation at said site in Ret thereby providing a modified Ret.
51. The method of claim 48, wherein said sub-structure comprises an attachment point for attaching a separate moiety.
52. The method of claim 51, wherein said separate moiety is selected from the group consisting of a peptide, a polypeptide, a solid phase material, a linker, and a label.
548
53. The method of claim 51, further comprising attaching said separate moiety.
54. A method for identifying potential Ret binding compounds, comprising fitting at least one electronic representation of a compound in an electronic representation, of a Ret or Ret surrogate binding site of a structure of Ret surrogate complexed with a binding compound.
55. The method of claim 54, wherein said electronic representation of a Ret or Ret surrogate binding site is defined by atomic structural coordinates set forth, in any of Tables 1-3.
56. The method of claim 54, comprising: removing a computer representation of said compound complexed with Ret or Ret surrogate and fitting a computer representation of a compound from a computer database with a computer representation of the active site of Ret or Ret surrogate; and identifying compounds that best fit said active site based on favorable geometric fit and energetically favorable complementary interactions as potential binding compounds.
57. The method of claim 54, comprising; modifying a computer representation of said compound complexed with Ret or Ret surrogate by the deletion or addition or both of one or more chemical groups; fitting a computer representation of a compound from a computer database with a computer representation of the active site of Ret or Ret surrogate; and identifying compounds that best fit said active site based on favorable geometric fit and energetically favorable complementary interactions as potential binding compounds.
58. The method of claim 54, comprising: removing a computer representation of a compound complexed with Ret or Ret surrogate; and searching a database for compounds having structural similarity to said compound using a compound searching computer program or replacing portions of said compound with similar chemical structures using a compound construction computer program.
59. The method of claim 54, wherein said compound complexed with Ret surrogate is a compound of Formula I, wherein:
Formula T is
549
Figure imgf000015_0001
Formula I
R1 and R5 are independently hydrogen, halo, hydroxy, optionally substituted alkoxyl, optionally substituted thioalkoxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclo alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -C(X)NR16R17, -C(X)R20, or -NR22R23;
R2, R3, and R4 are independently hydrogen, halo, hydroxy, optionally substituted alkoxyl, optionally substituted thioalkoxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl. optionally substituted heteroaryl, or optionally substituted heteroaralkyl, -C(X)R20, -C(X)NR16R17, -S(O)2NR16R*7, -NR22R23 , or -S(O)nR21;
R16 and R17 are independently hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or R16 and R17 together form a 5-7 membered carbocyclic or heterocyclic ring;
R20 is hydroxyl, optionally substituted lower alkoxy, optionally substituted amine, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaxyl, or optionally substituted heteroaralkyl;
R21 is hydrogen, optionally substituted lower alkyl, optionally substituted amine, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl- optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl;
550 R22 and R23 are independently hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaxyl, optionally substituted heteroaralkyl, -C(X)R20, -C(X)NR16R17, Or -S(O)2R21;
R24 is optionally substituted lower alkyl optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; and n = 0. I, or2.
60. The method of claim 54, wherein said fitting comprises determining whether a said compound will interact with one or more of conserved Ret active site residues.
61. A method for attaching a Ret binding compound to an attachment component, Comprising: identifying energetically allowed sites for attachment of a said attachment component on a kinase binding compound; and attaching said compound or derivative thereof to said attachment component at said energetically allowed site.
62. The method of claim 61, wherein said attachment component is a linker for attachment to a solid phase medium, and said method further comprises attaching said compound or derivative to a solid phase medium through a linker attached at a said energetically allowed site,
63. The method of claim 61, wherein said kinase comprises conserved residues matching at least one conserved Ret active site residues,
64. The method of claim 62, wherein said linker is a traceless linker.
65. The method of claim 61, wherein said kinase binding compound or derivative thereof is synthesized on a said linker attached to said solid phase medium.
66. The method of claim 65, wherein a plurality of said compounds or derivatives are synthesized in combinatorial synthesis.
551
67. The method of claim 61, wherein attachment of said compound to said solid phase medium provides an affinity medium.
68. The method of claim 61, wherein said attachment component comprises a label.
69. The method of claim 68, wherein said label comprises a fluorophore.
70. A modified compound, comprising a Ret binding compound, with a linker moiety attached thereto at an energetically allowed site for binding of said modified compound to Ret,
71. The compound of claim 70, whereins said linker is attached to a solid phase.
72. The compound of claim 70, wherein said linker comprises or is attached to a label.
,
73. The compound of claim 70, wherein said linker is a traceless linker.
74. A method for developing ligands binding to Ret, comprising: identifying as molecular scaffolds one or more compounds that bind to a binding site of Ret; determining the orientation of at least one molecular scaffold in co-crystals with Ret or Ret surrogate; identifying chemical structures of said molecular scaffolds, that, when modified, alter the binding affinity or binding specificity or both between the molecular scaffold and Ret; and synthesizing a ligand wherein one or more of the chemical structures of the molecular scaffold is modified to provide a ligand that binds to Ret with altered binding affinity or binding specificity or both.
75. The method of claim 74, wherein said molecular scaffold is a weak binding compound,
76. The method of claim 74, wherein said molecular scaffold binds to a plurality of kinases.
77. The method of claim 74, wherein said molecular scaffold includes the core structure of Formula I, wherein:
Formula I is
552
Figure imgf000018_0001
Formula I
R1 and R5 are independently hydrogen, halo, hydroxy, optionally substituted alkoxyl, optionally substituted thioalkoxy, optionally substituted lower alkyl, optionally substituted lower alketvyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -C(X)NR16R17, -C(X)R20,or -NR22R23;
R2, R3, and R4 are independently hydrogen, halo, hydroxy, optionally substituted alkoxyl, optionally substituted thioalkoxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterooycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl, -C(X)R20, -C(X)NR16R17, -S(O)2NR16R17, -NR22R23 , or -S(O)nR21;
R16 and R17 are independently hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or R16 and R17 together form a 5-7 membered carbocyclic or heterocyclic ring;
R20 is hydroxy!, optionally substituted lower alkoxy, optionally substituted amine, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;
R21 is hydrogen, optionally substituted lower alkyl, optionally substituted amine, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl;
553 R22 and R23 are independently hydrogen, optionally substituted lower allcyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyL, optionally substituted heteroaryi, optionally substituted heteroaralkyl, -C(X)R20, -C(X)KR16R17, or -S(O)2R21;
R24 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryi, or optionally substituted heteroaralkyl; and n = 0, 1, OΓ 2.
78. A method for developing ligands specific for Ret, comprising: identifying a compound that binds to a plurality of kinases; and determining whether a derivative of said compound has greater specificity for Ret than said compound.
79. The method of claim 78, wherein said compound binds to Ret with an affinity at least 10-fold greater than for binding to any of said plurality of kinases.
80. The method of claim 78, wherein said compound interacts with at least one conserved Ret active site residue,
81. The method of claim 78, wherein said compound binds weakly to said plurality of kinases.
82. The method of claim 78, wherein said plurality of kinases comprises Ret and FGFRl.
83. The method of claim 78, wherein said plurality of kinases comprises Ret, FGFR1, FGFR2, FGFR3, and FGFR4.
84. An electronic representation of a crystal structure of Ret surrogate, containing atomic coordinate representations corresponding to Ret binding site atoms,
85. The electronic representation of claim 84, comprising a schematic representation.
86. The electronic representation of claim 84, wherein said Ret surrogate comprises a Ret binding site sequence.
554
87. A FGFR-based homology model for Ret, comprising an atomic coordinate set derived by replacing FGFR amino acids with corresponding Ret residues.
88. A method for modeling binding of a compound in Ret kinase binding site, comprising modeling binding of a said compound in binding site of of a Ret surrogate.
89. The method of claim 88, wherein said Ret surrogate comprises a FGFR sequence substituted with at least 6 corresponding Ret amino acids.
90. A Ret surrogate protein, comprising a FGFR kinase domain sequence modified by the substitution of at least 4 binding site amino acid residues to amino acids present at the corresponding sites in Ret.
91. The Ret surrogate protein of claim 90, wherein said Ret surrogate comprises the amino acid substitutions of Ret Surrogate L
92. The Ret surrogate protein of claim 90, wherein said Ret surrogate comprises the amino acid substitutions of Ret Surrogate 2.
93 The Ret surrogate protein of claim 92, wherein said Ret surrogate comprises the substitution of Ret binding site sequence for corresponding FGFR binding site sequence.
555
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