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

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.