Carole Beaulieu

Design and synthesis of a novel class of histone deacetylase inhibitors

Histone deacetylase inhibitors (HDACs) have emerged as a novel class of antiproliferative agents. Utilizing structure-based design, the synthesis of a series of sulfonamide hydroxamic acids is described. Further optimization of this series by substitution of the terminal aromatic ring yielded HDAC inhibitors with good in vitro and in vivo activities.

Discovery of a novel and potent series of thieno[3,2-b]pyridine-based inhibitors of c-Met and VEGFR2 tyrosine kinases

A series of thieno[3,2-b]pyridine-based inhibitors of c-Met and VEGFR2 tyrosine kinases is described. The compounds demonstrated potency with IC(50) values in the low nanomolar range in vitro while the lead compound also showed in vivo activity against various human tumor xenograft models in mice. Further exploration of this class of compounds is underway.

N-(4-(6,7-Disubstituted-quinolin-4-yloxy)-3-fluorophenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides: A novel series of dual c-Met/VEGFR2 receptor tyrosine kinase inhibitors

A series of N-(4-(6,7-disubstituted-quinolin-4-yloxy)-3-fluorophenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides targeting c-Met and VEGFR2 tyrosine kinases was designed and synthesized. The compounds were potent against these two enzymes with IC(50) values in the low nanomolar range in vitro, possessed favorable pharmacokinetic profiles and showed high efficacy in vivo in several human tumor xenograft models in mice.

N-(3-fluoro-4-(2-arylthieno[3,2-b]pyridin-7-yloxy)phenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides: a novel series of dual c-Met/VEGFR2 receptor tyrosine kinase inhibitors.

A series of N-(3-fluoro-4-(2-arylthieno[3,2-b]pyridin-7-yloxy)phenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides targeting c-Met and VEGFR2 tyrosine kinases was designed and synthesized. The compounds were potent against these two enzymes with IC(50) values in the low nanomolar range in vitro, possessed favorable pharmacokinetic profiles and showed high efficacy in vivo in several human tumor xenograft models in mice.

N3-Arylmalonamides: A new series of thieno[3,2-b]pyridine based inhibitors of c-Met and VEGFR2 tyrosine kinases

A family of thieno[3,2-b]pyridine based small molecule inhibitors of c-Met and VEGFR2 were designed based on lead structure 2. These compounds were shown to have IC(50) values in the low nanomolar range in vitro and were efficacious in human tumor xenograft models in mice in vivo.

Identification of a novel series of potent RON receptor tyrosine kinase inhibitors

A novel series of N-(3-fluoro-4-(2-substituted-thieno[3,2-b]pyridin-7-yloxy)phenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamides targeting RON receptor tyrosine kinase was designed and synthesized. SAR study of the series allowed us to identify compounds possessing either inhibitory activity of RON kinase enzyme in the low nanomolar range with low residual activity against the closely related c-Met or potent dual inhibitory activity against RON and c-Met, with no significant activity against VEGFR2 in both cases.

Identification of potent and selective VEGFR receptor tyrosine kinase inhibitors having new amide isostere headgroups

A novel series of malonamide-type dual VEGFR2/c-Met inhibitors in which one of the amide bonds was replaced by an amide isostere-a trifluoroethylamine unit, was designed, synthesized, and evaluated for their enzymatic and cellular inhibition of VEGFR2 and c-Met enzymes. Optimization of these molecular entities resulted in identification of potent and selective inhibitors of VEGFR2 enzyme.

Abstract 3612: Potent preclinical anti-tumor activity of MGCD265, an orally active Met/VEGFR multitargeted kinase inhibitor in Phase II clinical development, in combination with an EGFR inhibitor

MGCD265 is an oral multitargeted receptor tyrosine kinase inhibitor in Phase II clinical development. MGCD265 targets the Met receptor tyrosine kinase and blocks Met activities which contribute to cancer development and progression such as cell proliferation, motility/invasion, angiogenesis and tumor cell survival. Although there is a large body of literature supporting Met activities as key to epithelial-mesenchymal transition and tumorigenesis, it is now accepted that the coordination of Met signaling with other regulators is central to oncogenesis. Met engages in cross-talks with several membrane proteins including the EGFR. Met and EGFR are coexpressed on tumor cells and functionally cooperate to amplify activating signals. Moreover, in NSCLC, Met gene amplification or overexpression of HGF, has been identified as a major molecular mechanism through which tumors evade EGFR inhibition by specific inhibitors such as gefitinib and erlotinib. Taken together, these studies provide a compelling rationale for concomitantly inhibiting Met and EGFR. In the present study, we have analyzed the in vivo anti-tumor activity of MGCD265 in combination with an EGFR-specific inhibitor, erlotinib. We demonstrate that this combination achieves greater antitumor responses than treatment with either agent alone, in multiple xenografts including NSCLC models. This is observed in the absence of overt toxicity. Furthermore, the PK of MGCD265 and erlotinib was analyzed when the two agents were co-administered, and indicated that there are no drug-drug interactions. In addition, in a NSCLC xenograft model that expresses an EGFR mutant resistant to erlotinib (T790M), MGCD265 significantly improved the anti-tumor activity when combined with erlotinib. The mechanisms underlying efficient tumor growth inhibition by this combination are presently under investigation. Preliminary results suggest that in addition to downregulating Met activation, MGCD265 may modulate EGFR activation by inhibiting the expression of the EGFR ligands TGFα and EREG. These preclinical studies provide support for the clinical development of MGCD265 in combination with erlotinib. 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 3612.