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Bioorg Med Chem Lett. 2014 Sep 15;24(18):4546-4552. doi: 10.1016/j.bmcl.2014.07.071. Epub 2014 Aug 2.

Fragment-based identification and optimization of a class of potent pyrrolo[2,1-f][1,2,4]triazine MAP4K4 inhibitors.

Author information

1
Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
2
Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
3
Department of Biochemical and Cellular Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
4
Department of Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
5
Department of Molecular Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
6
Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States. Electronic address: ndubaku.chudi@gene.com.
7
Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States. Electronic address: chen.huifen@gene.com.

Abstract

MAP4K4 has been shown to regulate key cellular processes that are tied to disease pathogenesis. In an effort to generate small molecule MAP4K4 inhibitors, a fragment-based screen was carried out and a pyrrolotriazine fragment with excellent ligand efficiency was identified. Further modification of this fragment guided by X-ray crystal structures and molecular modeling led to the discovery of a series of promising compounds with good structural diversity and physicochemical properties. These compounds exhibited single digit nanomolar potency and compounds 35 and 44 achieved good in vivo exposure.

KEYWORDS:

Fragment-based lead discovery; Kinase inhibitors; MAP4K4; P-loop conformation; Pyrrolotriazine

PMID:
25139565
DOI:
10.1016/j.bmcl.2014.07.071
[Indexed for MEDLINE]

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