Continuous de novo fatty acid synthesis is a common feature of cancer required to meet the biosynthetic demands of a growing tumor. This process is controlled by the rate-limiting enzyme acetyl-CoA carboxylase (ACC), an attractive but traditionally intractable drug target. Here, we provide genetic and pharmacological evidence that in preclinical models ACC is required to maintain de novo fatty acid synthesis needed for growth and viability of non-small cell lung cancer (NSCLC). We describe the ability of ND-646—an allosteric inhibitor of the ACC enzymes ACC1 and ACC2 that prevents ACC subunit dimerization—to suppress fatty acid synthesis in vitro and in vivo. Chronic ND-646 treatment of xenograft and genetically engineered mouse models of NSCLC inhibited tumor growth. When administered as a single agent or in combination with the standard-of-care drug carboplatin, ND-646 markedly suppressed lung tumor growth in the Kras;Trp53−/− (also known as KRAS p53) and Kras;Stk11−/− (also known as KRAS Lkb1) mouse models of NSCLC. These findings demonstrate that ACC mediates a metabolic liability of NSCLC and that ACC inhibition by ND-646 is detrimental to NSCLC growth, supporting further examination of the use of ACC inhibitors in oncology.

Summary The incidence of hepatocellular carcinoma (HCC) is rapidly increasing due to the prevalence of obesity and non-alcoholic fatty liver disease, but the molecular triggers that initiate disease development are not fully understood. We demonstrate that mice with targeted loss of function point mutations within the AMP-activated protein kinase (AMPK) phosphorylation sites acetyl-CoA carboxylase 1 (ACC1 Ser79Ala) and ACC2 (ACC2 Ser212Ala) have increased liver de novo lipogenesis (DNL) and liver lesions. The same mutation in ACC1 also increases DNL and proliferation human liver cancer cells. Consistent with these findings, a novel, liver specific ACC inhibitor (ND-654), that mimics the effects of ACC phosphorylation, inhibits hepatic DNL and the development of HCC, improving survival of tumor-bearing rats when used alone and in combination with the multi-kinase inhibitor sorafenib. These studies highlight the importance of DNL and dysregulation of AMPK-mediated ACC phosphorylation in accelerating HCC and the potential of ACC inhibitors for treatment.

Simultaneous inhibition of the acetyl-CoA carboxylase (ACC) isozymes ACC1 and ACC2 results in concomitant inhibition of fatty acid synthesis and stimulation of fatty acid oxidation and may favorably affect the morbidity and mortality associated with obesity, diabetes, and fatty liver disease. Using structure-based drug design, we have identified a series of potent allosteric protein–protein interaction inhibitors, exemplified by ND-630, that interact within the ACC phosphopeptide acceptor and dimerization site to prevent dimerization and inhibit the enzymatic activity of both ACC isozymes, reduce fatty acid synthesis and stimulate fatty acid oxidation in cultured cells and in animals, and exhibit favorable drug-like properties. When administered chronically to rats with diet-induced obesity, ND-630 reduces hepatic steatosis, improves insulin sensitivity, reduces weight gain without affecting food intake, and favorably affects dyslipidemia. When administered chronically to Zucker diabetic fatty rats, ND-630 reduces hepatic steatosis, improves glucose-stimulated insulin secretion, and reduces hemoglobin A1c (0.9% reduction). Together, these data suggest that ACC inhibition by representatives of this series may be useful in treating a variety of metabolic disorders, including metabolic syndrome, type 2 diabetes mellitus, and fatty liver disease.

IB kinase (IKK) ␤ is essential for inflammatory cytokine-induced activation of nuclear factor B (NF-B). NF-B plays a pivotal role in the function of major cell types that contribute to the pathophysiological process of rheumatoid arthritis (RA). Here, we report the mechanism and the effect of the IKK␤ inhibitor N- (6-chloro-7-methoxy-9H-␤-carbolin-8-yl)-2-methylnicotinamide (ML120B), a ␤-carboline derivative, on NF-B signaling and gene activation in RA-relevant cell systems. ML120B is a potent, selective, reversible, and ATP-competitive inhibitor of IKK␤ with an IC 50 of 60 nM when evaluated in an IB␣ kinase complex assay. ML120B does not inhibit other IKK isoforms or a panel of other kinases. ML120B concentrationdependently inhibits tumor necrosis factor ␣ (TNF␣)-stimulated NF-B signaling via inhibition of IB␣ phosphorylation, degradation, and NF-B translocation into the nucleus. For the first time, we have demonstrated that in human fibroblast-like synoviocytes, TNF␣-or interleukin (IL)-1␤-induced monocyte chemoattractant protein-1 regulated on activation, normal T cell expressed and secreted and production is IKK␤-dependent. In addition, for the first time, we have demonstrated that lipopolysaccharide-or peptidoglycan-induced cytokine production in human cord blood-derived mast cells is IKK␤-dependent. In addition, in human chondrocytes, ML120B inhibited IL-1␤-induced matrix metalloproteinase production with an IC 50 of approximately 1 M. ML120B also blocked IL-1␤-induced prostaglandin E 2 production. In summary, ML120B blocked numerous NF-B-regulated cell responses that are involved in inflammation and destructive processes in the RA joint. Our findings support the evaluation of IKK␤ inhibitors as anti-inflammatory agents for the treatment of RA.

NDI‐010976, an allosteric inhibitor of acetyl‐coenzyme A carboxylases (ACC) ACC1 and ACC2, reduces hepatic de novo lipogenesis (DNL) and favorably affects steatosis, inflammation, and fibrosis in animal models of fatty liver disease. This study was a randomized, double‐blind, placebo‐controlled, crossover trial evaluating the pharmacodynamic effects of a single oral dose of NDI‐010976 on hepatic DNL in overweight and/or obese but otherwise healthy adult male subjects. Subjects were randomized to receive either NDI‐010976 (20, 50, or 200 mg) or matching placebo in period 1, followed by the alternate treatment in period 2; and hepatic lipogenesis was stimulated with oral fructose administration. Fractional DNL was quantified by infusing a stable isotope tracer, [1‐13C]acetate, and monitoring 13C incorporation into palmitate of circulating very low‐density lipoprotein triglyceride. Single‐dose administration of NDI‐010976 was well tolerated at doses up to and including 200 mg. Fructose administration over a 10‐hour period stimulated hepatic fractional DNL an average of 30.9 ± 6.7% (mean ± standard deviation) above fasting DNL values in placebo‐treated subjects. Subjects administered single doses of NDI‐010976 at 20, 50, or 200 mg had significant inhibition of DNL compared to placebo (mean inhibition relative to placebo was 70%, 85%, and 104%, respectively). An inverse relationship between fractional DNL and NDI‐010976 exposure was observed with >90% inhibition of fractional DNL associated with plasma concentrations of NDI‐010976 >4 ng/mL. Conclusion: ACC inhibition with a single dose of NDI‐010976 is well tolerated and results in a profound dose‐dependent inhibition of hepatic DNL in overweight adult male subjects. Therefore, NDI‐010976 could contribute considerable value to the treatment algorithm of metabolic disorders characterized by dysregulated fatty acid metabolism, including nonalcoholic steatohepatitis. (Hepatology 2017;66:324–334).