Enzyme modulators and treatments

Abstract

Novel compounds and methods of using those compounds for the treatment of inflammatory conditions, immunological disorders, hyperproliferative diseases, cancer, and diseases characterized by hyper-vascularization are provided. In a preferred embodiment, modulation of the activation state of kinases, including p38 kinase protein, abl kinase protein, bcr-abl kinase protein, braf kinase protein, VEGFR kinase protein, or PDGFR kinase protein, comprises the step of contacting said kinase protein with the novel compounds.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of: (1) Provisional Application Ser. No. 60 / 639,087 filed Dec. 23, 2004; (2) Provisional Application Ser. No. 60 / 638,986, filed Dec. 23, 2004; (3) Provisional Application Ser. No. 60 / 638,987, filed Dec. 23, 2004; (4) Provisional Application Ser. No. 60 / 638,968, filed Dec. 23, 2004; These four provisional applications are incorporated by reference herein. Enzyme Modulators for Treatment of Cancers and Hyperproliferative DiseasesFIELD OF THE INVENTION [0002] The present invention relates to novel kinase inhibitors and modulator compounds useful for the treatment of various diseases. More particularly, the invention is concerned with such compounds, kinase / compound adducts, methods of treating diseases, and methods of synthesis of the compounds. Preferrably, the compounds are useful for the modulation of kinase activity of C-Abl, c-Kit, VEGFR, PDGFR, Raf and P38 kinases and disease polymorphs thereof. B...

AI Technical Summary

Benefits of technology

[0011] The present invention describes novel potent and selective inhibitors of CAbl kinase, VEGFR2 / KDR kinase, and BRAF kinase. The compounds of this invention inhibit kinase activity in a novel way by binding into the “switch pocket” remote from the ATP-cofactor pocket with or without concomitant binding into the “DFG-in-conformation” pocket. X-ray structures determined from small molecule / BRAF co-crystals have confirmed this novel mode of binding to the kinase by the compounds of this present invention, and illustrate the novel features of this binding mode when compared to inhibitors which anchor or bind into the ATP pocket of BRAF kinase. The novel inhibitors of the present invention in some cases also exhibit a preference for inhibiting the oncogenic mutant form of a kinase (V599E-BRAF) and a sparing of normal wild-type kinase that lack the cancer-causing mutation, wherein the oncogenic mutation is a modification of a critical binding amino acid residue of the switch control pocket. An example of this profile has been identified for BRAF, wherein mutation of the valine 599 residue to a glutamic acid residue results in an oncogenic form of BRAF and for which it has been found that compounds of this invention inhibit the oncogenic mutant form of BRAF but not the wild type BRAF. This desirable feature of inhibitor selectivity enables the use of a BRAF inhibitor to treat mammalian cancer caused by mutant V559E BRAF kinase, while sparing the normal wildtype BRAF kinase present in non-cancerous cells. Enhanced safety and selectivity realized from this “wild-type kinase-sparing” provides safer inhibitors that target the cancer-causing forms of BRAF kinase.

[0013] The binding modality of the compounds of this invention is illustrated in FIG. 2. The unique feature is the necessary engagement of another binding domain within the kinase referred to as the switch pocket. Compounds of this invention uniquely and necessarily bind within the switch pocket, and optionally the “DFG-in conformation” domain, and optionally to the ATP binding domain hinge region. This unique binding modality confers upon compounds of this invention a novel mechanism to modulate kinase activity as well as significant advantages over previously described kinase inhibitors in achieving a therapeutically important degree of selectivity for the preferred target over inhibitors which occupy the ATP binding domain. The novel binding modality of the compounds of this invention also avoids mutations within the ATP binding domain which commonly confer resistance to inhibition by compounds which require interaction with the ATP binding domain.

Problems solved by technology

Mutations in the p21-Ras protein have been shown to be a major cause of dysregulation of this signaling pathway, leading to the development of human cancers.

This single site mutation is sufficient to render the mutated BRAF kinase constituitively active, resulting in signaling pathway dysregulation and human cancer.

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