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

ABSTRACT: 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 immu

SUBMITTER: Mowat J 

PROVIDER: S-EPMC11472321 | biostudies-literature | 2024 Oct

REPOSITORIES: biostudies-literature