Author: Liang, Xiaorong ; Oeh, Jason ; Chou, Kang-Jye ; Wong, Susan ; Sampath, Deepak ; Ly, Justin ; Le, Hoa ; Cheong, Jonathan ; Liederer, Bianca M. ; Wang, Leslie ; Dragovich, Peter S. ; Mukadam, Sophie

GNE-617 (N-(4-((3,5-difluorophenyl)sulfonyl)benzyl)imidazo[1,2-a]pyridine-6-carboxamide) is a potent, selective nicotinamide phosphoribosyltransferase (NAMPT) inhibitor being explored as a potential treatment for human cancers. Plasma clearance was low in monkeys and dogs (9.14 mL min^-1kg^-1 and 4.62 mL min^-1kg^-1, respectively) and moderate in mice and rats (36.4 mL min^-1kg^-1 and 19.3 mL min^-1kg^-1, respectively). Oral bioavailability in mice, rats, monkeys and dogs was 29.7, 33.9, 29.4 and 65.2%, respectively. Allometric scaling predicted a low clearance of 3.3 mL min^-1kg^-1 and a volume of distribution of 1.3 L kg^-1 in human. Efficacy (57% tumor growth inhibition) in Colo-205 CRC tumor xenograft mice was observed at an oral dose of 15 mg/kg BID (AUC = 10.4 µM h). Plasma protein binding was moderately high. GNE-617 was stable to moderately stable in vitro. Main human metabolites identified in human hepatocytes were formed primarily by CYP3A4/5. Transporter studies suggested that GNE-617 is likely a substrate for MDR1 but not for BCRP. Simcyp^® simulations suggested a low (CYP2C9 and CYP2C8) or moderate (CYP3A4/5) potential for drug-drug interactions. The potential for autoinhibition was low. Overall, GNE-617 exhibited acceptable preclinical properties and projected human PK and dose estimates.

27 Mar 2018·Oncotarget

Cross resistance to diverse anticancer nicotinamide phosphoribosyltransferase inhibitors induced by FK866 treatment

Article

Author: Tanuma, Sei-ichi ; Ogino, Yoko ; Uchiumi, Fumiaki ; Sato, Akira

Cross-resistance to drugs remains an unsolved problem in cancer chemotherapy. This study elucidates a molecular mechanism of cross-resistance to diverse inhibitors of nicotinamide phosphoribosyltransferase (NAMPT) with anticancer activity. We generated a variant of the human colon cancer cell line HCT116, HCT116R^FK866, which exhibited primary resistance to the potent NAMPT inhibitor FK866, and was approximately 1,000-fold less sensitive to the drug than the parental HCT116. HCT116R^FK866 was found to be cross-resistant to diverse NAMPT inhibitors, including CHS-828, GNE-617, and STF-118804. Whole-exon sequencing revealed two point mutations (H191R and K342R) in NAMPT in HCT116R^FK866, only one of which (K342R) was present in the parental HCT116. Importantly, the protein level, NAMPT enzyme activity, and intracellular NAD⁺ level were similar between HCT116R^FK866 and HCT116. Hence, we investigated NAMPT-binding partners in both cell lines by focused proteomic analyses. The amount of NAMPT precipitated with anti-NAMPT monoclonal antibody was much higher in HCT116R^FK866 than in the parental. Furthermore, in HCT116, but not in HCT116R^FK866, NAMPT was revealed to interact with POTE ankyrin domain family member E and beta-actin. Thus, these results suggest that NAMPT usually interacts with the two partner proteins, and the H191R mutation may prevent the interactions, resulting in resistance to diverse NAMPT inhibitors.

01 Feb 2015·Bioorganic & Medicinal Chemistry LettersQ4 · MEDICINE

Identification of nicotinamide phosphoribosyltransferase (NAMPT) inhibitors with no evidence of CYP3A4 time-dependent inhibition and improved aqueous solubility

Q4 · MEDICINE

Article

Author: Skelton, Nicholas ; Baumeister, Timm ; Wang, Zhongguo ; Zak, Mark ; Bair, Kenneth W ; Smith, Chase C ; Buckmelter, Alexandre J ; Fu, Bang ; Yuen, Po-Wai ; O'Brien, Thomas ; Ly, Justin ; Dragovich, Peter S ; Liederer, Bianca M ; Zhao, Guiling ; Clodfelter, Karl H ; Wang, Weiru ; Crocker, Lisa ; Ho, Yen-Ching ; Zhang, Lei ; Han, Bingsong ; Zheng, Xiaozhang ; Liu, Xiongcai ; Cheng, Eric ; Li, Guangkun ; Reynolds, Dominic J ; Tay, Suzanne ; Sampath, Deepak ; Lin, Jian ; Xiao, Yang

Herein we report the optimization efforts to ameliorate the potent CYP3A4 time-dependent inhibition (TDI) and low aqueous solubility exhibited by a previously identified lead compound from our NAMPT inhibitor program (1, GNE-617). Metabolite identification studies pinpointed the imidazopyridine moiety present in 1 as the likely source of the TDI signal, and replacement with other bicyclic systems was found to reduce or eliminate the TDI finding. A strategy of reducing the number of aromatic rings and/or lowering cLogD7.4 was then employed to significantly improve aqueous solubility. These efforts culminated in the discovery of 42, a compound with no evidence of TDI, improved aqueous solubility, and robust efficacy in tumor xenograft studies.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	US	Genentech, Inc.	19 Dec 2014

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