Abstract 4457: Open science medicinal chemistry: Towards a treatment for DIPG

Abstract

Abstract Meds4Kids Pharma (M4K)1 is pioneering an open science approach to drug discovery, focussed on the discovery and development of small molecule therapeutics for orphan paediatric cancers. M4K seeks to test the hypothesis that an open science framework can be successfully applied not only to accelerate basic science, using the collective knowledge of the scientific community at large, but also to take an innovative new drug candidate all the way from discovery and clinical proof-of-concept through to product registration, by making use of regulatory data protections and market incentives. Since late 2017, Charles River Early Discovery has been providing in kind drug discovery services to help progress these efforts, including medicinal and synthetic chemistry. The first M4K project aims to generate an orally-available, brain-penetrant therapeutic to treat the diffuse intrinsic pontine glioma (DIPG). DIPG is a rare, aggressive and uniformly fatal childhood brain cancer with a median survival time of 9-12 months and for which there are currently no effective drug treatments. The disease has been shown to be associated with mutations in the ACVR1 gene (activin A receptor, type 1) also known as ALK2 kinase. Early support for the therapeutic hypothesis that an inhibitor of ALK2 kinase would have clinical benefit in DIPG, came from in vivo studies with non-selective ALK2 kinase inhibitors, which both killed DIPG cell lines harbouring the ALK2 mutation and extended lifespan in xenograft mouse models.2 Working collaboratively with M4K and their open science partners, we have made excellent progress towards the identification of potent, selective, brain penetrant ALK2 inhibitors starting from the known inhibitor LDN-214117, previously described for FOP (fibrodysplasia ossificans progressiva).3 Our current lead compound has an excellent in vitro and in vivo profile showing high oral bioavailability and brain penetration in a mouse PK study and is progressing to proof of concept studies. In addition we are progressing with the identification of a back-up series.