Abstract 463: GRC 54276, a novel small molecule inhibitor of HPK1 has entered phase 1/2 clinical trial insolid malignancies and Hodgkin’s/non Hodgkin’s lymphoma

Abstract

Abstract Background: Pre-clinical profile of GRC 54276, a clinical candidate with Phase 1/2 clinical trial ongoing, is presented here. GRC 54276 is a novel small molecule inhibitor of Hematopoietic progenitor kinase 1 (HPK1), a serine/threonine kinase1,2 that negatively regulates T and B cell receptor signaling3. Inhibition of HPK1 is an attractive therapeutic strategy for immuno-oncology based treatment of solid tumors3. Methods: GRC 54276 was designed and developed using SAR based medicinal chemistry design supported by computational approaches. In vitro profiling was done using a battery of biochemical assays, functional read-outs and primary human in vitro T-cell activation assays. In vivo efficacy was demonstrated in mouse colon tumor models of CT26 and MC38-hPD-L1. In vivo inhibition of biomarker pSLP76 Ser(376) by GRC 54276 was determined using CT26 tumor model. Detailed ADME-PK studies have been performed along with safety tolerability studies conducted in mice and monkeys. Results: GRC 54276, demonstrated excellent in vitro immune profile of target engagement and anti-tumor immune response activity in both human and mouse systems. As a single agent, GRC 54276 demonstrated strong inhibition of tumor growth and biomarker pSLP76 Ser(376) in the CT26 tumor model. Enhanced efficacy was demonstrated by combining GRC 54276 with check-point blocking antibodies anti-CTLA4 and Atezolizumab in the CT26 and MC38-hPD-L1 models, respectively. GRC 54276 robustly enhanced complete tumor rejections when combined with Atezolizumab in the MC38-hPD-L1 model, correlating with increased immune effector memory T cells. Pharmacokinetic profile of GRC 54276 is characterized by high permeability, rapid absorption and moderate oral bioavailable across species. GRC 54276 is non-gentoxic with no observed adverse effects in mice and no treatment related cardiovascular or respiratory effects in repeat dose toxicity study in monkeys. Conclusions: GRC 54276 is a novel HPK1 inhibtitor with acceptable pre-clincial profile and is currently undergoing a Phase 1/2 clinical trial. Acknowledgements: We thank Pooja S, Shital M, Rahul B, Ajit J, Sanjay G, Somesh K, Pramod S for their contributions to the project