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Bioorg Med Chem Lett. 2017 Apr 15;27(8):1709-1713. doi: 10.1016/j.bmcl.2017.02.079. Epub 2017 Mar 2.

Structure-based drug design of novel ASK1 inhibitors using an integrated lead optimization strategy.

Author information

1
Medicinal Chemistry Gastrointestinal Drug Discovery Unit, Takeda California Inc., 10410 Science Center Drive, San Diego, CA 92121, United States. Electronic address: tony.gibson@takeda.com.
2
Medicinal Chemistry CNS Drug Discovery Unit, Takeda California Inc., 10410 Science Center Drive, San Diego, CA 92121, United States.
3
Discovery Biology Gastrointestinal Drug Discovery Unit, Takeda California Inc., 10410 Science Center Drive, San Diego, CA 92121, United States.
4
Structural Biology and Biophysics, Takeda California Inc., 10410 Science Center Drive, San Diego, CA 92121, United States.
5
Medicinal Chemistry Gastrointestinal Drug Discovery Unit, Takeda California Inc., 10410 Science Center Drive, San Diego, CA 92121, United States.

Abstract

Structure-based drug design is an iterative process that is an established means to accelerate lead optimization, and is most powerful when integrated with information from different sources. Herein is described the use of such methods in conjunction with deconstruction and re-optimization of a diverse series of ASK1 chemotypes along with high-throughput screening that lead to the identification of a novel series of efficient ASK1 inhibitors displaying robust MAP3K pathway inhibition.

KEYWORDS:

Apoptosis signal-regulating kinase 1 (ASK1); Structure-based drug design (SBDD)

PMID:
28291695
DOI:
10.1016/j.bmcl.2017.02.079
[Indexed for MEDLINE]

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