| Popis: |
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 References: 1. F.Kiefer et al., The EMBO Journal 1996 2. Hu et al., Genes and Development 1996 3. Sawasdikosol and Burakoff. eLife 2020;9:e55122 Citation Format: Sravan Mandadi, Sanjib Das, Malini Bajpai, Jagmohan Saini, Murugan Chinnapattu, Sanjay Patale, Sandip Patil, Nanasaheb Kadlag, Nayan Waghmare, Balasaheb Gavhane, Ameya Deshpande, Dnyaneshwar Dahale, Vidya Kattige, Priyanka Pangre, Namrata Singh, Ekta Kashyap, Megha Marathe, Jiju Mani, Atul Akarte, Chandrasekhar Misra, Subhadip Das, Anuj Singh, Pandurang Lambade, Avratanu Das, Chaitanya Tirumalasetty, Raju Patole, Nilanjana Biswas, Vikas Karande, Heta Shah, Dayanidhi Behera, Pankaj Jain, Pavankumar Sancheti, Pramod Pawar, Vinod KR, Venkatesha Udupa, Sachin S. Chaudhari, Nagaraj Gowda, Pravin S. Iyer. 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]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 463. |
