Synactix Pharmaceuticals I-Corps Application

DESCRIPTION provided by applicant Polypharmacology represents a new and attractive approach to treat malignances as lasting and robust efficacy could be obtained through the inhibition of multiple survival pathways with one therapeutic agent In line with this method we have designed a RET rearranged during transfection VEGFR vascular endothelial growth factor receptor small molecule inhibitor that can shut down RET prosurvival signaling and VEGFR mediated angiogenesis With this agent the root of oncogenic signaling within RET driven tumors can be shut down as well as the ability for a tumor to acquire nutrients through VEGFR The inhibitor can achieve activity on RET VEGFR and all clinically relevant RET mutations at IC s of nM Through a PO mg kg day dose the inhibitor can block growth and cause RET driven xenografts to shrink Astonishingly at a PO mg kg day dose all treated tumors recede to undetectable levels in days In xenograft models highly predictive of clinical activity our agent is andgt times more active than similar agents We determined inhibition of both RET and VEGFR in tumor xenografts and found at PO mg kg our agent completely blocks RET and VEGFR activity Signaling to RET and VEGFR adaptor proteins and activation of the MAPK cascade is inhibited as well Pathway inhibition of both RET and VEGFR has been correlated to observed efficacy The inhibitor was found to be bioavailable in rats with a T of hours The agent was minimally active on hERG with IC of M CYP A with IC M and CYP D with IC M Inhibition of proliferative growth and proliferative signals was found highly selective for RET driven tumors GI s for RET driven tumors were typically andlt nM No adverse effect was identified in a day toxicity study at PO mg kg day in mice indicating a large therapeutic window The agent achieves activity on all ten clinically relevant RET mutations tested including gatekeeper mutations at IC s nM We believe the unique properties of our agent to simultaneously block all RET driven tumor growth and suppress VEGFR mediated nutrient accumulation is responsible for the unparalleled efficacy which could result in improved patient survival In this proposal we wish to further develop our RET VEGFR dual inhibitor by completing pilot formulation PK PD and toxicity studies This will acquire pivotal data necessary to justify completing an investigative new drug IND package Although we have established a robust andapos proof of conceptandapos data package specific facets to preclinical development are lacking that warrant additional pre IND development With the completion of this proposal we will have a data package that will merit full IND development PUBLIC HEALTH RELEVANCE A dual RET VEGFR tyrosine kinase inhibitor has been identified that can potentially offer cancer patients a more effective treatment The inhibitor is considerably more safe and effective over previous treatments in the same class The completion of the proposed research will help this breakthrough medicine reach patients quickly and safely