Abstract 1646: Development of small-molecule HPK1 inhibitors to unleash tumor-specific T cell responses
| Autor: | Scott Jacobson, Jeffrey R. Jackson, Daniel Poon, Michelle Ko, Paul D. Kassner, Mikhail Zibinsky, Paul Leger, Heather Milestone, Deepika Kaveri, Anqi Ma, Thant Zaw, Lan Nguyen, Yamini M. Ohol, Tivitmahaisoon Parcharee, Chandru Ramana, Martin Brovarney, Delia Bradford, Cynthia Cho, Michael Sun, Lavanya Adusumilli, Jerick Sanchez, George E. Katibah, Omar Robles, Dan Nebalasca, Steve Wong, Blanca Gomez, Justy Gomez Guagua, Cyril Bucher, Rachel Ames, Mengshu Xu, David J. Wustrow, Anton Shakhmin, Andrew Ng, Dirk G. Brockstedt, Grant M. Shibuya, Molly Grandcolas |
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| Rok vydání: | 2021 |
| Předmět: | |
| Zdroj: | Cancer Research. 81:1646-1646 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | Hematopoietic progenitor kinase 1 (HPK1) is an intracellular protein kinase that negatively regulates T cell signaling and proliferation. Upon T cell receptor (TCR) activation, active HPK1 phosphorylates the adaptor protein SLP76 in the TCR complex, recruiting the negative regulator 14-3-3 and targeting components of the TCR signaling complex for degradation. HPK1 thus limits the TCR signaling important for mounting an effective immune response against tumor cells. We are employing structure-guided drug design to develop potent small-molecule inhibitors of HPK1. Our compounds potently inhibit HPK1 in biochemical assays, reduce levels of phosphorylated SLP76 and concomitantly increase IL-2 production by Jurkat T cells. Importantly, our HPK1 inhibitors enhance cytokine production by human and mouse primary T cells above that observed with TCR activation alone. Treatment of mice with orally available HPK1 inhibitors results in increased activation of antigen-specific CD8+ T cells in vivo and decreased tumor growth as single agent and in combination with clinically relevant checkpoint inhibitor antibodies. Our work confirms the importance of HPK1 for T cell function and supports HPK1 as a promising next generation immuno-oncology target. Citation Format: George Katibah, Yamini Ohol, Cyril Bucher, Lavanya Adusumilli, Deepika Kaveri, Omar Robles, Michael Sun, Cynthia Cho, Heather Milestone, Rachel Ames, Scott Jacobson, Dan Nebalasca, Justy Gomez- Guagua, Jerick Sanchez, Molly Grandcolas, Steve Wong, Martin Brovarney, Chandru Ramana, Thant Zaw, Lan Nguyen, Parcharee Tivitmahaisoon, Andrew Ng, Anqi Ma, Blanca Gomez, Michelle Ko, Paul Leger, Jeffrey Jackson, Grant Shibuya, Anton Shakhmin, Delia Bradford, Mengshu Xu, Mikhail Zibinsky, Daniel Poon, David Wustrow, Paul Kassner, Dirk Brockstedt. Development of small-molecule HPK1 inhibitors to unleash tumor-specific T cell responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1646. |
| Databáze: | OpenAIRE |
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