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685 A highly selective and potent HPK1 inhibitor enhances immune cell activation and induces robust tumor growth inhibition in a murine syngeneic tumor model
  1. David Ciccone1,
  2. Vad Lazari2,
  3. Ian Linney2,
  4. Michael Briggs2,
  5. Samantha Carreiro1,
  6. Joshua McElwee1,
  7. Ian Waddell2,
  8. Chris Hill2,
  9. Christine Loh1,
  10. Peter Tummino1,
  11. Alan Collis1 and
  12. Neelu Kaila1
  1. 1Nimbus Therapeutics, Cambridge, MA, USA
  2. 2Charles River Laboratories, Chesterford Research Park, UK


Background HPK1, a member of the MAP4K family of protein serine/threonine kinases, is involved in regulating signal transduction cascades in cells of hematopoietic origin. Recent data from HPK1 knockout animals and kinase-inactive knock-in animals underscores the role of HPK1 in negatively regulating immune cell activation. This negative-feedback role of HPK1 combined with its restricted expression in cells of hematopoietic origin, make it a compelling drug target for enhancing anti-tumor immunity.

Methods A structure-based drug design approach was used to identify potent and selective inhibitors of HPK1. Biochemical assays, as well as primary human and mouse immune cell-based activation assays, were utilized for multiple iterations of structure-activity relationship (SAR) studies. In vivo efficacy, target engagement and pharmacodynamic data were generated using murine syngeneic tumor models.

Results A highly potent, HPK1 inhibitor was identified, that showed high selectivity against T cell-specific kinases and kinases in the MAP4K family. In vitro, HPK1 small molecule inhibition resulted in enhanced IL-2 production in primary mouse and human T cells, enhanced IL-6 and IgG production in primary human B cells, and enhanced mouse dendritic cell activation and antigen presentation capacity. Furthermore, HPK1 inhibition alleviated the immuno-suppressive effects of PGE2 on naïve human T cells and restored the proliferative capacity of exhausted human T cells. In vivo, HPK1 inhibitionHPK1 inhibition abrogated T cell receptor-stimulated phospho-SLP-76, enhanced cytokine production, and mediated robust tumor growth inhibition in a murine syngeneic tumor model.

Conclusions Pharmacological blockade of HPK1 kinase activity represents a novel and potentially valuable immunomodulatory approach for anti-tumor immunity.

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