JMKX007129是一种靶向N端结构域的新一代雄激素受体抑制剂，用于治疗转移性去势抵抗性前列腺癌

Background: Androgen receptor ligand binding domain (AR LBD) mutations are one of the key factors leading to resistance to AR inhibitors or degraders in castration-resistant prostate cancer (CRPC). As a result, inhibitors targeting other domains of AR, such as the NTD, have become a major focus in current drug development efforts to overcome this resistance. However, the clinical development of Anitens-based AR-NTD inhibitors has encountered setbacks due to insufficient activity and selectivity. Therefore, there is an urgent need to develop AR-NTD inhibitors with higher potency, improved selectivity, and enhanced safety profiles. Methods: Based on the core structure of Anitens, we conducted rational design and obtained the lead compound JMKX007129. A comprehensive suite of in vitro and in vivo characterizations was subsequently performed. These evaluations included assessments of its target binding affinity, mechanism of action, in vitro and in vivo efficacy, pharmacokinetic and toxicological profiles, as well as its combination effects with existing AR inhibitors and degraders. Results: Compound JMKX007129 demonstrated excellent in vitro and in vivo activity and selectivity. Cellular Thermal Shift Assay (CETSA) confirmed that JMKX007129 simultaneously engages both full-length AR (in LnCap cells) and the splice variant AR-V7 (in 22RV1 cells). Reporter gene and qPCR assays demonstrated that JMKX007129 effectively (EC50≈20 nM) modulates the transcription of downstream genes of both AR and AR-V7. It potently inhibited the proliferation of AR-positive prostate cancer cells, exhibiting a selectivity window of approximately 20-fold over AR-negative cells. JMKX007129 displayed favorable pharmacokinetic properties in mice, rats, and dogs, which translated into robust in vivo antitumor efficacy. Significant activity was observed in models sensitive to AR inhibitors (LnCap) as well as in those with acquired resistance (VCap, 22RV1), accompanied by a favorable tolerability profile. Finally, JMKX007129 exhibited a synergistic anti-proliferative effect in combination with AR inhibitors or degraders in 22RV1 cells. Conclusions: In summary, we have successfully developed JMKX007129, a novel small-molecule compound targeting the AR-NTD. Preclinical studies demonstrate that JMKX007129, both as a monotherapy and in combination with AR inhibitors or degraders, exhibits promising in vitro and in vivo efficacy and a favorable safety profile, indicating its potential to overcome resistance mediated by AR LBD mutations. IND-enabling studies for JMKX007129 are currently underway.