Abstract LB-268: Discovery of clinical candidate methyl (5-(6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate (CYH33) : A highly potent and selective PI3K alpha inhibitor for the treatment of advanced solid tumors
Authors: Xiang Haoyue , Wang Xiang , Chen Yanhong , Zhang Xi , Chen Yi , Tan Cun , Wang Yi , Ding Jian , Meng Ling-Hua , Yang Chunhao 
Published: August 2018

Phosphatidylinositol 3-kinaseα isoform (PI3Kα) is frequently deregulated in a wide variety of human solid tumors. A series of new pyrrolo[2,1-f][1,2,4]triazines has been prepared in an effort to discover new PI3Kα-selective inhibitors. Intensive structure-activity relationship (SAR) and structure-pharmacokinetic relationship (SPR) studies on this new series led to the discovery of compound 40 (CYH33), a potent and highly selective PI3Kα inhibitor. CYH33 displays the most potent activity against PI3Kα among the class I PI3K isoforms, with IC50s of 5.9 nM/598 nM/ 78.7 nM/225 nM against α/β/δ/γ isoform respectively. Kinome profiling revealed that CYH33 showed little activity among more than 300 kinases. The selectivity of CYH33 against PI3Kα was further confirmed with a panel of Rh30-Myr-p110s isogenic cells, which express constitutively active PI3K isoform respectively. Accordingly, CYH33 inhibited PI3K/AKT/mTOR signaling in glioblastoma U87MG and rhabdomyosarcoma Rh30 cells, which is associated with its potent anti-proliferative activity in against cell proliferation in a panel cancer cell lines originated from breast, lung, ovary and colon, prostate etc. It is noteworthy that most of sensitive cells were originated from breast cancer, which was consistent with the fact that PI3K is frequently hyper-activated in breast cancer. Oral administration of CYH33 to mice bearing ovarian cancer SKOV-3 xenografts resulted in decreased phosphorylation of AKT in tumor tissue, which is consistent with the significant efficacy of CYH33 to inhibit the growth of SKOV-3 xenograft. Moreover, CYH33 did not cause significant weight loss and toxic symptoms during the treatment period. We also detected the glucose tolerance after mice bearing SKOV-3 xenografts were administered with CYH33 for 18 days. Though CYH33 treatment delayed the restoration of blood glucose to normal level, blood glucose of the CYH33-treated groups were similar to that of control group 2 h after the injection of glucose. CYH33 displays a favorable pharmacokinetic profile with an oral bioavailability of 36.9% and little activity against the major cytochrome P450 isozymes. In summary, CYH33 emerged as a novel selective PI3Kα inhibitor with potent activity against human solid tumors and favorable pharmaceutical profile, which makes it a promising drug candidate and enter clinical trials in China.

Citation Format: Haoyue Xiang, Xiang Wang, Yanhong Chen, Xi Zhang, Yi Chen, Cun Tan, Yi Wang, Jian Ding, Ling-Hua Meng, Chunhao Yang. Discovery of clinical candidate methyl (5-(6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate (CYH33) : A highly potent and selective PI3K alpha inhibitor for the treatment of advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-268.