Bioevaluation Of K-80003 Derivatives And Their Mechanism Of Anti-cancer Action

Retinoid X receptor-alpha(RXRα),a key member of the nuclear receptor superfamily,plays a critical regulatory role in various physiological processes including proliferation,differentiation,survival and apoptosis.Altered expression,subcellular localization,or function of RXRa is closely related to the development of cancers.Therefore,RXRa is a well-established drug target,representing one of the most valuable targets for pharmacologic interventions and therapeutic applications for cancer therapy.Breast cancer presents one of the highest rates of prevalence among all types of cancer in women.Triple negative breast cancer(TNBC)remains the most challenging breast cancer subtype.Traditional first-line chemotherapy drugs have severe toxic and side effects and are easy to relapse.So far,there is no targeted therapy for this type of cancer.Molecular targeted drugs with low toxicity and high effectiveness is urgently needed.Sulindac derivatives K-80003 can bind RXRa to inhibit the interaction of truncated RXRα(tRXRα)with the p85α subunit of PI3K to inhibit cancer cell survival.At present,K-80003 has been approved by FDA as an anti-tumor drug to enter clinical trial.Based on K-80003,our goal was to develop more efficient,low-toxic K-80003-derived anti-tumor drugs.In this study,24 candidate K-80003 derivatives were evaluaed for their the anti-triple-negative breast cancer activity and RXRa targeting.Our evaluation identified XS-594 as the most effective candidate with the highest binding ability to RXRa and the best anti-breast cancer activity.XS-594 significantly inhibited the proliferation of TNBC and induced tumor cell apoptosis,which are partially depended on the expression of RXRα.In the breast cancer xenograft model,XS-594 significantly inhibited the growth of MDA-MB-231 xenograft tumors with no visible toxic effects.Mechanistic studies showed that XS-594 induced cell cycle arrest at the G0/G1 phase and induced autophagy.The mTOR signaling pathway is frequently activated in TNBC.We found that XS-594 inhibited mTOR activation in a RXRα-dependent manner.XS-594 could inhibit the interaction of p62 and TRAF6,providing a plausible mechanism for its anti-mTOR effect.Together,our identification of XS-594 with potent anti-TNBC activity and our illustration of its mechanism of action provide new strategies to develop new anti-TNBC targeted drugs.