ND-646 is 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.
ND-646 simultaneously inhibits ACC1 and ACC2, thus preventing ACC2 from compensating for the inhibition of ACC1. ND-646 inhibits the dimerization of the hACC2-BC domain under native conditions. In a cell-free system, ND-646 inhibits the enzymatic activity of hACC1 with an IC50 of 3.5 nM and hACC2 with an IC50 of 4.1 nM[1].
ND-646 动物研究
Animal study
To assess the effects of prolonged ND-646 treatment on NSCLC tumor progression and to evaluate the impact of bi-daily administration, athymic nude mice with established A549 subcutaneous tumors received oral treatments of either a control vehicle twice daily (BID), ND-646 at 25 mg/kg once daily (QD), ND-646 at 25 mg/kg BID, or ND-646 at 50 mg/kg QD over a span of 31 days. The 25 mg/kg QD dosage of ND-646 proved ineffective in curbing tumor growth. In contrast, ND-646 at 25 mg/kg BID or 50 mg/kg QD markedly reduced the growth of subcutaneous A549 tumors. Throughout the treatment duration, ND-646 was well-tolerated, with no notable weight loss observed, indicating that the maximum tolerated dose (MTD) was not surpassed. Following the final dose, mice were euthanized after 1 hour, and their tissues were processed for either immunohistochemistry (IHC) or immunoblot analysis. Tumors subjected to all ND-646 dosages exhibited a loss of p-ACC detection at 1 hour, confirming effective tumor infiltration and immediate ACC inhibition by ND-646. Importantly, a significant increase in p-EIF2αS51 expression within tumor extracts was only observed at ND-646 dosages that significantly impeded tumor growth (25 mg/kg BID and 50 mg/kg QD)[1].
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