ADT Pharmaceuticals, LLC — Department of Health and Human Services SBIR Phase I: NCI

Description

Mutations in the ras family of genes were first identified in human cancer overyears agoSuch mutations may result in the constitutive activation of one or more of three major Ras protein isoformsincluding H RasNRasor K Rasthat mediate important signaling pathways leading to uncontrolled cell growth and tumor developmentActivating mutations of ras genes occur de novo in approximately one third of all human cancers and are especially prevalent in colorectallungand pancreatic tumorsMutations in ras also arise in tumors that become resistant to chemotherapy and or radiationCurrently there are no available drugs approved by the U SFood and Drug Administration that can selectively suppress the growth of tumors driven by activated RasEmploying a cell based phenotypic screenADT Pharmaceuticals Inchas discovered a novel compound series that potently and selectively inhibits tumor cells harboring activated RasFollowing extensive chemical optimizationa preclinical development candidateDCwas identified that shows low nanomolar growth inhibitory ICvalues in tumor cells harboring activated Raswhile tumor cells lacking activated Rasand cells derived from normal tissuesare insensitiveData suggest that the drug interacts with Ras to disrupt Ras Raf interactions and suppress downstream signaling of both the Raf MAPK and PI K Akt pathwaysDCshows strong in vivo antitumor activity in a mouse xenograft model following i padministration with no discernible toxicity and attractive drug like properties feasible for oral deliveryHere we propose to develop an oral formulation to enable further preclinical development and will work closely with CatalentInca company with extensive formulation expertiseAimwill synthesize DCin bulk and extensively characterize the physiochemical properties of the compound in pre formulation studiesAimwill develop at leastunique formulations of DCand Aimwill determine the in vivo pharmacokinetic characteristics of the formulations and will select a final dose to be evaluated for tolerability in miceWe anticipate a clinical development candidate in an optimal formulation for oral delivery will emerge from this project that will be advanced to a Phase II SBIR application involving further preclinical development to optimize dose and scheduleGMP scale up synthesisand GLP toxicity assessment to support an IND application for human clinical trials in patients with Ras driven cancers