Liu Bee Hui, Liu Miao, Radhakrishnan Sridhar, Jaladanki Chaitanya Kumar, Gao Chong, Tang Jing Ping, Kumari Kalpana, Go Mei Lin, Vu Kim Anh L, Seo Hyuk-Soo, Song Kijun, Tian Xi, Feng Li, Tan Justin L, Bassal Mahmoud A, Arthanari Haribabu, Qi Jun, Dhe-Paganon Sirano, Fan Hao, Tenen Daniel G, Chai Li
bioRxiv. 2024 Jan 3:2024.01.03.574032. doi: 10.1101/2024.01.03.574032.
Immunomodulatory imide drugs (IMiDs) degrade specific C2H2 zinc finger degrons in transcription factors, making them effective against certain cancers. SALL4, a cancer driver, contains seven C2H2 zinc fingers in four clusters, including an IMiD degron in zinc finger cluster two (ZFC2). Surprisingly, IMiDs do not inhibit growth of SALL4 expressing cancer cells. To overcome this limit, we focused on a non-IMiD degron, SALL4 zinc finger cluster four (ZFC4). By combining AlphaFold and the ZFC4-DNA crystal structure, we identified a potential ZFC4 drug pocket. Utilizing an docking algorithm and cell viability assays, we screened chemical libraries and discovered SH6, which selectively targets SALL4-expressing cancer cells. Mechanistic studies revealed that SH6 degrades SALL4 protein through the CUL4A/CRBN pathway, while deletion of ZFC4 abolished this activity. Moreover, SH6 led to significant 62% tumor growth inhibition of SALL4+ xenografts in vivo and demonstrated good bioavailability in pharmacokinetic studies. In summary, these studies represent a new approach for IMiD independent drug discovery targeting C2H2 transcription factors in cancer.
免疫调节性酰亚胺药物（IMiDs）可降解转录因子中特定的C2H2锌指降解子，使其对某些癌症有效。癌症驱动因子SALL4在四个簇中包含七个C2H2锌指，其中锌指簇二（ZFC2）中含有一个IMiD降解子。令人惊讶的是，IMiDs并不抑制表达SALL4的癌细胞的生长。为了克服这一限制，我们聚焦于一个非IMiD降解子，即SALL4锌指簇四（ZFC4）。通过结合AlphaFold和ZFC4-DNA晶体结构，我们确定了一个潜在的ZFC4药物口袋。利用对接算法和细胞活力测定，我们筛选了化学文库并发现了SH6，它能选择性地靶向表达SALL4的癌细胞。机制研究表明，SH6通过CUL4A/CRBN途径降解SALL4蛋白，而ZFC4的缺失消除了这种活性。此外，SH6在体内导致SALL4+异种移植瘤的肿瘤生长显著抑制62%，并在药代动力学研究中显示出良好的生物利用度。总之，这些研究代表了一种针对癌症中C2H2转录因子的独立于IMiD的药物发现新方法。
