Preclinical assessment of the ADME, efficacy and drug-drug interaction potential of a novel NAMPT inhibitor
Creators: name: Liederer, Bianca M.
name: Cheong, Jonathan
name: Kang-Jye Chou
name: Dragovich, Peter S.
name: Le, Hoa
name: Xiaorong Liang
name: Ly, Justin
name: Mukadam, Sophie
name: Oeh, Jason
name: Sampath, Deepak
name: Wang, Leslie
name: Wong, Susan
Publisher: name: Taylor & Francis
Year: 2019
Subjects: subject: Biochemistry
subject: Cell Biology
subject: Physiology
subject: FOS: Biological sciences
subject: FOS: Biological sciences
subject: Pharmacology
subject: Biotechnology
subject: 59999 Environmental Sciences not elsewhere classified
subject: FOS: Earth and related environmental sciences
subject: FOS: Earth and related environmental sciences
subject: 39999 Chemical Sciences not elsewhere classified
subject: FOS: Chemical sciences
subject: FOS: Chemical sciences
subject: Immunology
subject: FOS: Clinical medicine
subject: FOS: Clinical medicine
subject: Cancer
subject: 111714 Mental Health
subject: FOS: Health sciences
subject: FOS: Health sciences
subject: Hematology
subject: 110309 Infectious Diseases
subject: 60506 Virology
subject: Computational Biology

description: GNE-617 (<i>N</i>-(4-((3,5-difluorophenyl)sulfonyl)benzyl)imidazo[1,2-<i>a</i>]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<sup>−1 </sup>kg<sup>−1</sup> and 4.62 mL min<sup>−1 </sup>kg<sup>−1</sup>, respectively) and moderate in mice and rats (36.4 mL min<sup>−1 </sup>kg<sup>−1</sup> and 19.3 mL min<sup>−1 </sup>kg<sup>−1</sup>, 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<sup>−1 </sup>kg<sup>−1</sup> and a volume of distribution of 1.3 L kg<sup>−1</sup> 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 <i>in vitro</i>. 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<sup>®</sup> 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. GNE-617 (<i>N</i>-(4-((3,5-difluorophenyl)sulfonyl)benzyl)imidazo[1,2-<i>a</i>]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<sup>−1 </sup>kg<sup>−1</sup> and 4.62 mL min<sup>−1 </sup>kg<sup>−1</sup>, respectively) and moderate in mice and rats (36.4 mL min<sup>−1 </sup>kg<sup>−1</sup> and 19.3 mL min<sup>−1 </sup>kg<sup>−1</sup>, 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<sup>−1 </sup>kg<sup>−1</sup> and a volume of distribution of 1.3 L kg<sup>−1</sup> 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 <i>in vitro</i>. 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<sup>®</sup> 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.