Franck Raeppel

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.

SAR around (l)-S-adenosyl-l-homocysteine, an inhibitor of human DNA methyltransferase (DNMT) enzymes

The inhibitory activity of base-modified SAH analogues and the specificity of inhibiting human DNMT1 and DNMT3b2 enzymes was explored. The 6-amino group was essential while the 7-N of the adenine ring of SAH could be replaced by CH- without loss of activity against both enzymes. The introduction of small groups at the 2-position of the adenine moiety favors DNMT1 over DNMT3b2 inhibition whereas alkylation of the N(6)-amino moiety favors the inhibition of DNMT3b2 enzyme.

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.

Synthesis of the trans-syn-trans perhydrobenz[e]indene moiety of the stellettins and of the stelliferins

Abstract The perhydrobenz[ e ]indene moiety of the stellettins and of the stelliferins, two families of isomalabaricane-type triterpenes with trans-syn-trans ring junctions, has been built from a bicyclic γ,δ-unsaturated aldehyde by a reaction sequence including a Lewis acid catalysed ene cyclisation to form a cyclopentanol, a hydroxyl-directed cyclopropanation, and the ring opening of a cyclopropyl ketone with trimethylsilyl iodide.

Design and synthesis of constrained analogs of LCRF-0004 as potent RON tyrosine kinase inhibitors

New fused bicyclic lactam head groups as rigidified analogs of thieno[3,2-b]pyridine-based kinase inhibitor LCRF-0004 were designed and synthesized. Depending on the functionalities and the size of these bicyclic head groups, potent inhibitors of RON tyrosine kinase with various level of selectivity against c-Met tyrosine kinase were obtained.

Abstract 930: Preclinical characterization of MG516, a novel inhibitor of receptor tyrosine kinases involved in resistance to targeted therapies.

Despite breakthroughs in the clinical development of tyrosine kinase inhibitors, challenges remain in overcoming resistance to these molecular targeted therapies. Advances in our understanding of mechanisms of resistance to targeted agents will improve patient outcome. While secondary mutations play a key role, the activation of parallel signaling pathways has been shown to alter the sensitivity to targeted inhibition. Resistance to inhibitors of the EGFR or VEGFR families may occur through the activation of Met, EphA2 and Axl receptor tyrosine kinase pathways, suggesting combined inhibition of these targets as a strategy to prevent resistance to approved EGFR- and VEGFRs -targeted therapies. We have developed a novel multitargeted receptor tyrosine kinase inhibitor, MG516, with nanomolar activities in in vitro enzymatic assays against members of the Eph receptor family, Axl, Met and VEGFR1,2,3. In carcinoma cell lines, MG516 potently inhibits phosphorylation of EphA2, Axl and Met. Inhibition of Met downstream signaling as well as the inhibition of Met-dependent biological endpoints, such as motility and wound healing is also achieved. In human umbilical vein endothelial cells (HUVECs),VEGFR2 activation and VEGF-dependent angiogenesis are blocked. Potent anti-tumor activity is demonstrated across a broad range of human xenograft models including lung, gastric, glioblastoma, colorectal and breast carcinomas. Anti-tumor activity is achieved at oral doses as low as 2.5mg/kg in the absence of overt toxicity, weight loss or myelosuppression. Immunohistochemistry analyses of xenograft tumors after treatment with MG516 reveal a decrease in the proliferation of tumor cells, a decrease in tumor vascularization, pharmacodynamic inhibition of target phosphorylation and decreases in target expression, including EphA2. Consistent with targeting multiple oncogenic pathways simultaneously, the combination of MG516 with EGFR inhibition results in improved tumor growth inhibition. Importantly, in a gastric cancer model exhibiting resistance to sunitinib following prolonged treatment with this agent, MG516 induces tumor regression. Thus, MG516 offers potential for clinical development of a novel therapeutic, by targeting a combination of oncogenic kinases involved in tumor development, progression and resistance to targeted therapies. Citation Format: Normand Beaulieu, Helene Sainte-Croix, Claire Bonfils, Michael Mannion, Stephane Raeppel, Lubo Isakovic, Stephen Claridge, Oscar Saavedra, Franck Raeppel, Arkadii Vaisburg, James Wang, Marielle Fournel, Jeffrey M. Besterman, Christiane R. Maroun. Preclinical characterization of MG516, a novel inhibitor of receptor tyrosine kinases involved in resistance to targeted therapies. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 930. doi:10.1158/1538-7445.AM2013-930

Design, synthesis and RON receptor tyrosine kinase inhibitory activity of new head groups analogs of LCRF-0004

New heteroarylcarboxamide head groups substituted with two aromatic rings analogs of thieno[3,2-b]pyridine-based kinase inhibitor LCRF-0004 were designed and synthesized. Potent inhibitors of RON tyrosine kinase with various level of selectivity for c-Met RTK were obtained.

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.

Conversion of a trans–syn–trans to a cis–syn–trans perhydrobenz[e]indenone triggered by intramolecular 1,5-hydrogen transfer

Abstract The conversion of a trans – syn – trans perhydroiodomethyltrimethylbenz[ e ]indenone to the corresponding cis – syn – trans perhydrobenz[ e ]indenone occurred during the reduction of the iodomethyl to a methyl group under radical conditions.