SELECTIVE SERINE/THREONINE KINASE INHIBITORS

• US 20100256171A1
• Filed: 02/01/2010
• Published: 10/07/2010
• Est. Priority Date: 04/11/2003
• Status: Active Grant

• Current Assignee: Regents of the University of California (University of California)
• Original Assignee: Regents of the University of California (University of California)
• Inventors: TAUNTON, JACK, COHEN, MICHAEL, SHOKAT, KEVAN, ZHANG, CHAO
• Granted Patent: US 8,034,821 B2
• Time in Patent Office: Days
• US Class Current: 514/265.100
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

Inhibition of protein kinases having one or more cysteine residues within the ATP binding site is effected by contacting the kinase, per se or in a cell or subject, with an inhibitory-effective amount of a compound having a heterocyclic core structure comprised of two or more fused rings containing at least one nitrogen ring atom, and an electrophilic substituent that is capable of reacting with a cysteine residue within the ATP binding site of a kinase.

Preferred compounds include certain pyrrolopyrimidines and oxindoles having such an electrophilic substituent and optionally an aromatic or heteroaromatic substituent that is capable of interacting with a threonine or smaller residue located in the gatekeeper position of the kinase.

Kinases lacking such cysteine residues may be engineered or modified so that they are capable of being inhibited by such compounds by replacing a valine or other amino acid residue within the ATP binding site by a cysteine residue.

Claims

1. A compound having the formula (I):

2. A compound according to claim 1 in which E is an electrophilic group that comprises a carbonyl, an epoxide, or an olefin conjugated to an electron withdrawing group.

3. A compound according to claim 1 in which R² is hydrogen.

4. A compound according to claim 1 in which R² is a group having the formula (CH₂)_bR^b.

5. A compound according to claim 4 in which R² is an optionally substituted phenyl group.

6. A compound according to claim 1 in which E comprises a carbonyl, an epoxide, or an olefin conjugated to an electron withdrawing group.

7. A compound according to claim 6 in which E comprises an olefin conjugated to a carbonyl, nitro, cyano, carboxyl, carboxamide, sulfoxide, sulfonyl, sulfonamide, or sulfonate group.

8. A compound according to claim 1 in which E comprises a carbonyl group.

9. A compound according to claim 8 in which the carbonyl group has the formula —

C(O)(CH₂)_nR in which R is a halogen and n is 0 or an integer from 1 to 6.

10. A compound according to claim 8 in which the carbonyl group has the formula —

(CH₂)_mC(O)R in which m is 0 or an integer from 1 to 6 and R is a halogen.

11. A compound according to claim 9 in which R is chloro.

12. A compound according to claim 9 in which R is fluoro.

13. A compound according to claim 8 in which the carbonyl group comprises an olefinically unsaturated ketone.

15. A method of inhibiting a protein kinase that has one or more cysteine residues within its ATP binding site, comprising contacting the kinase with an inhibitory-effective amount of a compound according to claim 1.

18. A method according to claim 16 in which the compound is a compound according to claim 1.

14. A method of inhibiting a protein kinase that has one or more cysteine residues within its ATP binding site, comprising contacting the kinase with an inhibitory-effective amount of a compound having a heterocyclic core structure comprised of two or more fused rings containing at least one nitrogen ring atom, and an electrophilic substituent that is capable of forming a covalent bond with a cysteine residue within the ATP binding site of a kinase.

16. A method for inhibiting the proliferation of a tumor cell comprising contacting the cell with an inhibitory-effective amount of a compound having a heterocyclic core structure comprised of two or more fused rings containing at least one nitrogen ring atom, and an electrophilic substituent that is capable of forming a covalent bond with a cysteine residue within the ATP binding site of a kinase.

17. A method according to claim 16 in which the compound is a pyrrolopyrimidine.