Discovery of\nBAY-405: An Azaindole-Based MAP4K1 Inhibitor\nfor the Enhancement of T‑Cell Immunity against Cancer

Mitogen-activated protein kinase kinase kinase kinase\n1 (MAP4K1)\nis a serine/threonine kinase that acts as an immune checkpoint downstream\nof T-cell receptor stimulation. MAP4K1 activity is enhanced by prostaglandin\nE2 (PGE2) and transforming growth factor beta (TGFβ), immune\nmodulators commonly present in the tumor microenvironment. Therefore,\nits pharmacological inhibition is an attractive immuno-oncology concept\nfor inducing therapeutic T-cell responses in cancer patients. Here,\nwe describe the systematic optimization of azaindole-based lead compound <b>1</b>, resulting in the discovery of potent and selective MAP4K1\ninhibitor <b>38</b> (BAY-405) that displays nanomolar potency\nin biochemical and cellular assays as well as in vivo exposure after\noral dosing. BAY-405 enhances T-cell immunity and overcomes the suppressive\neffect of PGE2 and TGFβ. Treatment of tumor-bearing mice shows\nT-cell-dependent antitumor efficacy. MAP4K1 inhibition in conjunction\nwith PD-L1 blockade results in a superior antitumor impact, illustrating\nthe complementarity of the single agent treatments.