Mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4), a serine/threonine protein kinase, is upregulated in many types of cancers. To study the function of MAP4K4 in vivo for oncology indications, a FBLD approach was initiated to identify a proof of concept tool compound. A screening of 2361 fragments at 100 µM as singletons using Surface Plasmon Resonance (SPR) led to 225 confirmed hits with LE &gt; 0.35. We followed up on multiple fragment hits initially and settled on two fragments for full optimization. Starting from a micromolar pyrrolotriazine fragment hit (1), we developed a series of single digit nanomolar inhibitors of MAP4K4 by utilizing crystal structures and molecular modeling. Several compounds in the pyrrolotriazine series also demonstrated favorable in vivo bioavailability in mouse. In parallel, we also worked on an oxazole fragment (2), and through scaffold hopping approach we obtained a novel and potent naphthyridine series of MAP4K4 inhibitors. These efforts resulted in the identification of compound G-495, which had excellent potency, kinase selectivity and mouse PK profile, providing a robust chemical probe for studying MAP4K4 biological function in vivo.

Fragment-based lead discovery of a novel Map4k4 inhibitor

253rd National Meeting (2017)

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