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Abstract
Background Despite the promise shown by the CPIs targeting the PD-1 or CTLA-4 axes, recent estimates of the percentage of responders to these CPI across different cancers has been modest. One of the causes for non-response is impaired capacity of invigoration of exhausted T cells. Haematopoietic Progenitor Kinase (HPK-1, MAP4K1), a member of the STE20 family of serine/threonine kinases, is expressed predominantly in hematopoietic cells. HPK-1 acts as a negative regulator of T-cell and B-cell receptor activation and triggers the proteasomal degradation and disrupts signalosome complexes downstream of TCR and BCR. Promising initial clinical results with novel HPK1 inhibitor have established HPK1 inhibition an attractive novel IO strategy that could combine with existing chemotherapies and immunotherapies
Materials and Methods Pharmacophore based approach was used to design and synthesize novel small molecule HPK-1 inhibitors using in vitro enzymatic and primary cell based phenotypic cellular screens. CRD1601, the clinical candidate was selected based on its ability to enhance human T-cell proliferation through the induction of IL2, IFNγ and TNFα. Syngeneic tumor models were used to assess anti-tumor activity.
Results CRD1601 is a potent single digit nanomolar HPK1 inhibitor as determined in enzymatic assay. It potently inhibits the phosphorylation of cellular SLP76 and leads to T cell activation and proliferation. Further, CRD1601 reversed the immunosuppressive effect of PGE2 and NECA on T cells. A single dose of CRD1601 in mice treated with an anti-CD3 antibody caused systemic enhancement of pro-inflammatory cytokines such as IL2, IFN gamma and reduced pSLP76 levels in the spleen. CRD1601 demonstrated significant single agent activity in multiple murine tumor models and also synergizes with chemotherapy and immunotherapy.
Conclusions HPK-1 inhibition is a promising therapeutic modality that could augment the effects of existing anti-cancer treatments. CRD1601 is a potent and selective HPK-1 inhibitor with favorable drug like properties which shows promising in vivo activity in multiple tumor models as single agent and in combination with existing therapies.
R. Shrivastava: A. Employment (full or part-time); Significant; Curadev pharma pvt ltd. M. Banerjee: A. Employment (full or part-time); Significant; Curadev pharma pvt ltd. D. Pryde: A. Employment (full or part-time); Significant; Curadev pharma pvt ltd, UK. S. Middya: A. Employment (full or part-time); Significant; Curadev pharma pvt ltd. S. Debnath: A. Employment (full or part-time); Significant; Curadev pharma pvt ltd. A. Middya: A. Employment (full or part-time); Significant; Curadev pharma pvt ltd. D. Yadav: A. Employment (full or part-time); Significant; Curadev pharma pvt ltd. N. Mane: A. Employment (full or part-time); Significant; Curadev Pharma Pvt. Ltd. N. Rawat: A. Employment (full or part-time); Significant; Curadev pharma pvt ltd. R. Ghosh: A. Employment (full or part-time); Significant; Curadev pharma pvt ltd. A. Gautam: A. Employment (full or part-time); Significant; Curadev pharma pvt ltd. M. Padaliya: A. Employment (full or part-time); Modest; Curadev pharma pvt ltd. S. Bano: A. Employment (full or part-time); Modest; Curadev pharma pvt ltd. S. Basu: A. Employment (full or part-time); Significant; Curadev pharma pvt ltd. A. Surya: A. Employment (full or part-time); Significant; Curadev pharma pvt ltd. E. Ownership Interest (stock, stock options, patent or other intellectual property); Significant; Curadev pharma pvt ltd.
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