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Overview

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Neoplasms

Respiratory Diseases

Endocrinology and Metabolic Disease

Small molecule drug

Disease domain score

A glimpse into the focused therapeutic areas

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Most used technologies in drug development

Targets

Most frequently developed targets

Disease Domain	Count

Neoplasms	2
Endocrinology and Metabolic Disease	1

Top 5 Drug Type	Count

Small molecule drug	2

Top 5 Target	Count

SHP2(Src homology phosphotyrosyl phosphatase 2)	1
ALK x c-Met	1

The anaplastic lymphoma kinase (ALK) and the c-Met receptor tyrosine kinase play essential roles in the pathogenesis in multiple human cancers and present emerging targets for cancer treatment. Here, we describe CM-118, a novel lead compound displaying low nanomolar biochemical potency against both ALK and c-Met with selectivity over>90 human kinases. CM-118 potently abrogated hepatocyte growth factor (HGF)-induced c-Met phosphorylation and cell migration, phosphorylation of ALK, EML4-ALK, and ALK resistance mutants in transfected cells. CM-118 inhibited proliferation and/or induced apoptosis in multiple c-Met- and ALK-addicted cancer lines with dose response profile correlating target blockade. We show that the CM-118-induced apoptosis in c-Met-amplified H1993 NSCLC cells involved a rapid suppression of c-Met activity and c-Met-to-EGFR cross-talk, and was profoundly potentiated by EGFR inhibitors as shown by the increased levels of apoptotic proteins cleaved-PARP and Bim as well as reduction of the survival protein Mcl-1. Bim-knockdown or Mcl-1 overexpression each significantly attenuated apoptosis. We also revealed a key role by mTOR in mediating CM-118 action against the EML4-ALK-dependent NSCLC cells. Abrogation of EML4-ALK in H2228 cells profoundly reduced signaling capacity of the rapamycin-sensitive mTOR pathway leading to G 1 cell cycle arrest and mitochondrial hyperpolarization, a metabolic perturbation linked to mTOR inhibition. Depletion of mTOR or mTORC1 inhibited H2228 cell growth, and mTOR inhibitors potentiated CM-118's antitumor activity in vitro and in vivo. Oral administration of CM-118 at a wide range of well tolerated dosages diminished c-Met- and ALK phosphorylation in vivo, and caused tumor regression or growth inhibition in multiple c-Met- and ALK-dependent tumor xenografts in mice. CM-118 exhibits favorable pharmacokinetic and drug metabolism properties hence presents a candidate for clinical evaluation.

15 Apr 2010·Cancer Research

Abstract 1788: Preclinical development of a selective, potent small molecule ALK inhibitor

Author: Pao, William ; Lovly, Christine M. ; de Stanchina, Elisa ; Liang, Chris

AbstractA chromosomal inversion [inv (2)(p21p23)] resulting in the expression of an oncogenic kinase fusion protein known as EML4-ALK [echinoderm microtubule-associated protein-like 4- anaplastic lymphoma kinase] has been implicated in the pathogenesis of a subset of lung adenocarcinomas. An agent (PF-02341066), originally described as a MET tyrosine kinase inhibitor (TKI) but with “off-target” ALK activity, has demonstrated significant activity in ALK-fusion positive lung cancer patients and is currently in phase II/III clinical trials. In this study, we describe the development and characterization of a novel and highly selective ALK TKI. X-276 (racemic mixture) is an orally bioavailable ATP mimetic that has high selectivity for ALK as assessed by Ambit assays (binding constant 2nM). Treatment of H3122 lung adenocarcinoma cells, which harbor the EML4-ALK E13;A20 fusion product, resulted in potent inhibition of cell growth with an IC50 of 10nM, approximately 10 fold less than the IC50 of H3122 cells treated with a racemic mixture of PF-02341066. Immunoblot analysis confirmed that X-276 inhibited ALK phosphorylation in H3122 cells. Importantly, the IC50 of X-276 in H1993 lung cancer cells, known to be MET-dependent, was >100 fold higher. In addition, the selectivity index of H3122 cells vs. hepatocyte HepG2 cells was >135. Finally, compared to vehicle controls, X-276 delayed the growth of H3122 xenografts in established nude mice by >60%. Collectively, these data show that TKIs can be developed with greater specificity against ALK. Such compounds may lead to the development of ‘second-generation’ ALK TKIs with more potency against ALK-mutant cancers. Future studies will focus on determining the mechanism of acquired resistance to ALK TKIs using these more potent ALK inhibitors.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1788.

100 Deals associated with Xcovery, Inc.

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100 Translational Medicine associated with Xcovery, Inc.

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Pipeline

Pipeline Snapshot as of 06 Feb 2025

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

Phase 1 Clinical

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Current Projects

Drug(Targets)	Indications	Global Highest Phase

CM-118 ( ALK x c-Met )	Non-Small Cell Lung Cancer More	Phase 1
BPI-442096 ( SHP2 )	Solid tumor More	Phase 1
X-370 ( PI3Kδ )	Acute Lymphoblastic Leukemia More	Pending
Cancer and inflammation therapeutics(Xcovery) ( ALK )	Neoplasms More	Pending
XV-615 ( PDGFR x VEGFR2 )	Eye Diseases More	Pending