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

Abstract MGCD265 is a multitargeted receptor tyrosine kinase inhibitor in Phase II clinical development, which inhibits the activation of regulators of cancer development and progression by targeting Met, the three members of the VEGFR family, Tie-2 and Ron. Met is a key player in the epithelial-mesenchymal transition (EMT) and Met deregulation is described in several types of cancer. The mechanisms involved in Met activation include co-expression of Met with its ligand HGF, overexpression of the Met protein, Met and/or HGF gene amplification or activating mutations. Originally found in hereditary papillary renal carcinoma (HPRCC), activating missense mutations in the kinase domain provided the first evidence that Met activation was causative of this disease. Mutations outside of the tyrosine kinase domain, such as those in the juxtamembrane and extracellular sema domains have also been analyzed, and found in NSCLC, SCLC, melanoma, head and neck cancer, mesothelioma and pancreatic cancer. For the clinical development of MGCD265, we demonstrated the ability of MGCD265 to inhibit clinically relevant Met mutants described in a variety of cancers, including HPRCC and NSCLC. In cell-based assays, MGCD265 inhibits the activation of Met kinase domain mutants (e.g. Y1230C) as well as mutants within the juxtamembrane region (e.g. R988C), and the extracellular domain (e.g. N375S) with nanomolar potency. This is of particular interest, as several kinase domain mutations confer resistance of Met to Met-selective agents such as PF-4217903. MGCD265 also inhibits signaling pathways activated downstream from Met mutants. The phosphorylation of Gab1 multisubstrate docking protein following the activation of Met mutants is inhibited by MGCD265 as is the ensuing activation of the Erk pathway. Furthermore, MGCD265 inhibits the motility of renal carcinoma cells expressing an extracellular domain Met mutant, and blocks tumor growth in a NSCLC cell line expressing a juxtamembrane domain Met mutant. These results, together with our previous findings, demonstrate that MGCD265 is particularly efficient at inhibiting tumor growth in animal models in which wild-type Met or Met mutants are active, suggesting that MGCD265 may particularly benefit patients with activated Met. 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 3609.

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.

Cette invention porte sur des composes qui inhibent l'activite de proteine tyrosine kinase. En particulier, l'invention porte sur des composes qui inhibent l'activite de proteine tyrosine kinase de recepteurs de facteurs de croissance, ce qui entraine l'inhibition de la signalisation des recepteurs, par exemple l'inhibition de la signalisation des recepteurs du VEGF. L'invention porte egalement sur des composes, des compositions et des procedes pour traiter des maladies et affections proliferatives des cellules et des maladies, troubles et affections ophtalmologiques.

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.

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.

Alternative and Complementary TherapiesVol. 3, No. 3 Historical Perspective Wilhelm Reich, 1897–1957A Reevaluation for a New GenerationMichael MannionMichael MannionSearch for more papers by this authorPublished Online:3 Feb 2009https://doi.org/10.1089/act.1997.3.194AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail FiguresReferencesRelatedDetailsCited byÜber die Beziehung von therapeutischen Empfindungen und Lebensenergie-Konzepten – von Huang Di zu Wilhelm Reich17 June 2021 | Chinesische Medizin / Chinese Medicine, Vol. 36, No. 2 Volume 3Issue 3Jun 1997 To cite this article:Michael Mannion.Historical Perspective Wilhelm Reich, 1897–1957.Alternative and Complementary Therapies.Jun 1997.194-199.http://doi.org/10.1089/act.1997.3.194Published in Volume: 3 Issue 3: February 3, 2009PDF download