用于癌症治疗的ACC1选择性抑制剂的设计、合成与药理学评价

Acetyl-CoA carboxylase (ACC) is an enzyme that regulates the rate-limiting step in lipid synthesis, converts acetyl-CoA to malonyl-CoA, and is attracting attention as a drug discovery target in a wide range of areas, including metabolic diseases, oncology, and immunology. There are two subtypes of ACC, and among them, ACC1 has been reported to be highly expressed in human cancer cells, and is therefore expected to be a candidate for the development of new cancer therapeutics. Aiming to develop novel and selective ACC1 inhibitors, we initiated synthetic development from pyrrolopyridine derivative and benzoxazole derivative as lead compounds. In terms of pyrrolopyridine derivative, modification of substituents dramatically improved ACC1 inhibitory activity and PK profiles to identify in vivo tool compound which showed potent PD activity. On the other hand, in benzoxazole derivative, linkers and terminal parts were developed for improving enzymatic activity. As a result, we found 2-phenylbenzoxazole compound, which exhibits very strong selective ACC1 inhibitory activity. Furthermore, we continued to investigate reducing lipophilicity to improve solubility toward the generation of in vivo tool compounds, and found ureido compound with good selective ACC1 inhibitory activity and PK profiles. This compound showed significant anti-tumor efficacy in 786-O xenograft mice at an oral dose of 30 mg/kg, bid (T/C = 0.5%) along with potent and prolonged PD activity. Further investigation toward ACC1 specific inhibitor discovered monocyclic derivatives. Among them, oxazole compound exhibited more potent in vivo efficacy than ureido compound in several xenograft mice models. This finding was the first example to show anti-tumor efficacy by the treatment with ACC1 specific inhibitor as a single agent.