Discovery of BAY-405: An Azaindole-Based MAP4K1 Inhibitor for the Enhancement of T‑Cell Immunity against Cancer

• Published in: Journal of medicinal chemistry 2024-10, Vol.67 (19), p.17429-17453
• Main Authors: Mowat, Jeffrey, Carretero, Rafael, Leder, Gabriele, Aiguabella Font, Nuria, Neuhaus, Roland, Berndt, Sandra, Günther, Judith, Friberg, Anders, Schäfer, Martina, Briem, Hans, Raschke, Marian, Miyatake Ondozabal, Hideki, Buchmann, Bernd, Boemer, Ulf, Kreft, Bertolt, Hartung, Ingo V., Offringa, Rienk
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Aza Compounds - chemical synthesis; Aza Compounds - chemistry; Aza Compounds - pharmacology; Cell Line, Tumor; Drug Discovery; Female; Humans; Indoles - chemistry; Indoles - pharmacology; Mice; Mice, Inbred C57BL; Neoplasms - drug therapy; Neoplasms - immunology; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - metabolism; Structure-Activity Relationship; T-Lymphocytes - drug effects; T-Lymphocytes - immunology
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.4c01325

Mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1) is a serine/threonine kinase that acts as an immune checkpoint downstream of T-cell receptor stimulation. MAP4K1 activity is enhanced by prostaglandin E2 (PGE2) and transforming growth factor beta (TGFβ), immune modulators commonly present in the tumor microenvironment. Therefore, its pharmacological inhibition is an attractive immuno-oncology concept for inducing therapeutic T-cell responses in cancer patients. Here, we describe the systematic optimization of azaindole-based lead compound 1, resulting in the discovery of potent and selective MAP4K1 inhibitor 38 (BAY-405) that displays nanomolar potency in biochemical and cellular assays as well as in vivo exposure after oral dosing. BAY-405 enhances T-cell immunity and overcomes the suppressive effect of PGE2 and TGFβ. Treatment of tumor-bearing mice shows T-cell-dependent antitumor efficacy. MAP4K1 inhibition in conjunction with PD-L1 blockade results in a superior antitumor impact, illustrating the complementarity of the single agent treatments.