Discovery of potent and efficacious cyanoguanidine-containing nicotinamide phosphoribosyltransferase (Nampt) inhibitors

Xiaozhang Zheng; Timm Baumeister; Alexandre J Buckmelter; Maureen Caligiuri; Karl H Clodfelter; Bingsong Han; Yen-Ching Ho; Nikolai Kley; Jian Lin; Dominic J Reynolds; Geeta Sharma; Chase C Smith; Zhongguo Wang; Peter S Dragovich; Angela Oh; Weiru Wang; Mark Zak; Yunli Wang; Po-Wai Yuen; Kenneth W Bair

doi:10.1016/j.bmcl.2013.11.006

Discovery of potent and efficacious cyanoguanidine-containing nicotinamide phosphoribosyltransferase (Nampt) inhibitors

Bioorg Med Chem Lett. 2014 Jan 1;24(1):337-43. doi: 10.1016/j.bmcl.2013.11.006. Epub 2013 Nov 14.

Authors

Xiaozhang Zheng¹, Timm Baumeister², Alexandre J Buckmelter², Maureen Caligiuri², Karl H Clodfelter², Bingsong Han², Yen-Ching Ho², Nikolai Kley², Jian Lin², Dominic J Reynolds², Geeta Sharma², Chase C Smith², Zhongguo Wang², Peter S Dragovich³, Angela Oh³, Weiru Wang³, Mark Zak³, Yunli Wang⁴, Po-Wai Yuen⁴, Kenneth W Bair²

Affiliations

¹ Forma Therapeutics, Inc., 500 Arsenal Street, Watertown, MA 02472, USA. Electronic address: xzheng@formatherapeutics.com.
² Forma Therapeutics, Inc., 500 Arsenal Street, Watertown, MA 02472, USA.
³ Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
⁴ Pharmaron Beijing, Co. Ltd, 6 Tai He Road, BDA, Beijing 100176, PR China.

PMID: 24279990
DOI: 10.1016/j.bmcl.2013.11.006

Abstract

A co-crystal structure of amide-containing compound (4) in complex with the nicotinamide phosphoribosyltransferase (Nampt) protein and molecular modeling were utilized to design and discover a potent novel cyanoguanidine-containing inhibitor bearing a sulfone moiety (5, Nampt Biochemical IC50=2.5nM, A2780 cell proliferation IC50=9.7nM). Further SAR exploration identified several additional cyanoguanidine-containing compounds with high potency and good microsomal stability. Among these, compound 15 was selected for in vivo profiling and demonstrated good oral exposure in mice. It also exhibited excellent in vivo antitumor efficacy when dosed orally in an A2780 ovarian tumor xenograft model. The co-crystal structure of this compound in complex with the NAMPT protein was also determined.

Keywords: Nampt; Nicotinamide phosphoribosyltransferase; X-ray crystal structure; cyanoguanidine.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / administration & dosage
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Proliferation / drug effects
Cytokines / antagonists & inhibitors*
Cytokines / metabolism
Dose-Response Relationship, Drug
Drug Discovery*
Enzyme Inhibitors / administration & dosage
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Female
Guanidines / administration & dosage
Guanidines / chemistry
Guanidines / pharmacology*
Humans
Mice
Models, Molecular
Molecular Structure
Neoplasms, Experimental / drug therapy*
Nicotinamide Phosphoribosyltransferase / antagonists & inhibitors*
Nicotinamide Phosphoribosyltransferase / metabolism
Ovarian Neoplasms / drug therapy*
Structure-Activity Relationship
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Cytokines
Enzyme Inhibitors
Guanidines
Nicotinamide Phosphoribosyltransferase
nicotinamide phosphoribosyltransferase, human
dicyandiamido