Discovery of a Series of Orally Bioavailable Androgen Receptor Degraders for the Treatment of Prostate Cancer

Androgen receptor (AR) signaling plays a key role in
the progression
of prostate cancer. This study describes the discovery and optimization
of a novel series of AR PROTAC degraders that recruit the Cereblon
(CRBN) E3 ligase. Having identified a series of AR ligands based on
4-(4-phenyl-1-piperidyl)-2-(trifluoromethyl)benzonitrile, our PROTAC
optimization strategy focused on linker connectivity and CRBN ligand
SAR to deliver potent degradation of AR in LNCaP cells. This work
culminated in compounds 11 and 16 which
demonstrated good rodent oral bioavailability. Subsequent SAR around
the AR binding region brought in an additional desirable feature,
degradation of the important treatment resistance mutation L702H.
Compound 22 (AZ′3137) possessed an attractive
profile showing degradation of AR and L702H mutant AR with good oral
bioavailability across species. The compound also inhibited AR signaling
in vitro and tumor growth in vivo in a mouse prostate cancer xenograft
model.

雄激素受体（Androgen Receptor, AR）信号通路在前列腺癌的进展中发挥关键作用。本研究报道了一类新型AR蛋白降解靶向嵌合体（Proteolysis Targeting Chimera, PROTAC）降解剂的发现与优化过程，该类降解剂可募集CRBN蛋白（Cereblon, CRBN）E3泛素连接酶。本研究以4-(4-苯基-1-哌啶基)-2-(三氟甲基)苯甲腈为母核筛选得到一系列AR配体，随后的PROTAC优化策略聚焦于连接臂连接方式与CRBN配体的构效关系（Structure-Activity Relationship, SAR），最终在人前列腺癌细胞系LNCaP中实现了AR的高效降解。本研究最终得到化合物11与16，二者在啮齿类动物中表现出良好的口服生物利用度。后续针对AR结合区域的构效关系研究新增了一项理想特性：可降解临床治疗中重要的耐药突变体L702H。化合物22（AZ′3137）具备优异的成药特性：可降解AR及L702H突变型AR，且在不同物种中均表现出良好的口服生物利用度。该化合物在体外可抑制AR信号通路，在小鼠前列腺癌异种移植模型中可有效抑制体内肿瘤生长。