1. Academic Validation
  2. Potent GCN2 Inhibitor Capable of Reversing MDSC-Driven T Cell Suppression Demonstrates In Vivo Efficacy as a Single Agent and in Combination with Anti-Angiogenesis Therapy

Potent GCN2 Inhibitor Capable of Reversing MDSC-Driven T Cell Suppression Demonstrates In Vivo Efficacy as a Single Agent and in Combination with Anti-Angiogenesis Therapy

  • J Med Chem. 2022 Oct 13;65(19):12895-12924. doi: 10.1021/acs.jmedchem.2c00736.
Jeffrey J Jackson 1 Grant M Shibuya 1 Buvana Ravishankar 1 Lavanya Adusumilli 1 Delia Bradford 1 Dirk G Brockstedt 1 Cyril Bucher 1 Minna Bui 1 Cynthia Cho 1 Christoph Colas 1 Gene Cutler 1 Adrian Dukes 1 Xinping Han 1 Dennis X Hu 1 Scott Jacobson 1 Paul D Kassner 1 George E Katibah 1 Michelle Yoo Min Ko 1 Urvi Kolhatkar 1 Paul R Leger 1 Anqi Ma 1 Lisa Marshall 1 Jack Maung 1 Andrew A Ng 1 Akinori Okano 1 Deepa Pookot 1 Daniel Poon 1 Chandru Ramana 1 Maureen K Reilly 1 Omar Robles 1 Jacob B Schwarz 1 Anton A Shakhmin 1 Hunter P Shunatona 1 Raashi Sreenivasan 1 Parcharee Tivitmahaisoon 1 Mengshu Xu 1 Thant Zaw 1 David J Wustrow 1 Mikhail Zibinsky 1
Affiliations

Affiliation

  • 1 RAPT Therapeutics, 561 Eccles Avenue, South San Francisco, California94080, United States.
Abstract

General control nonderepressible 2 (GCN2) protein kinase is a cellular stress sensor within the tumor microenvironment (TME), whose signaling cascade has been proposed to contribute to immune escape in tumors. Herein, we report the discovery of cell-potent GCN2 inhibitors with excellent selectivity against its closely related Integrated Stress Response (ISR) family members heme-regulated inhibitor kinase (HRI), protein kinase R (PKR), and (PKR)-like endoplasmic reticulum kinase (PERK), as well as good kinome-wide selectivity and favorable PK. In mice, compound 39 engages GCN2 at levels ≥80% with an oral dose of 15 mg/kg BID. We also demonstrate the ability of compound 39 to alleviate MDSC-related T cell suppression and restore T cell proliferation, similar to the effect seen in MDSCs from GCN2 knockout mice. In the LL2 syngeneic mouse model, compound 39 demonstrates significant tumor growth inhibition (TGI) as a single agent. Furthermore, TGI mediated by anti-VEGFR was enhanced by treatment with compound 39 demonstrating the complementarity of these two mechanisms.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-151460
    99.85%, GCN2 Inhibitor