Kimani Serah W, Noureldin Mahmoud, Wilson Brian, Hoffer Laurent, Green Stuart R, Szewczyk Magdalena M, González-Álvarez Héctor, Mohammed Mohammed, Chan Manuel, Krausser Chiara, Li Alice Shi Ming, Hajian Taraneh, Tucker Sarah, Joshi Dhananjay, Saraon Punit, Thériault Brigitte, Kim Ji Sup, Santhakumar Vijayaratnam, Loppnau Peter, Li Yanjun, Seitova Almagul, Dong Aiping, Kiyota Taira, Hammann Tobias, Gehrtz Paul, Patel Bhashant, Rathod Vaibhavi, Vala Anand, Rout Bhimsen, Jagodra Paras, Brown Peter J, Aman Ahmed, Ramnauth Jailall, Poda Gennady, Uehling David, Arrowsmith Cheryl H, Barsyte-Lovejoy Dalia, Marcellus Richard, Ackloo Suzanne, Mamai Ahmed, Al-Awar Rima, Halabelian Levon
Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada.
Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, Canada.
Commun Biol. 2025 Jul 19;8(1):1076. doi: 10.1038/s42003-025-08491-0.
Human DCAF1 is a multidomain protein that plays a critical role in protein homeostasis. Its WDR domain functions as a substrate recruitment module for RING-type CRL4 and HECT family EDVP E3 ubiquitin ligases, enabling the ubiquitination and proteasomal degradation of specific substrates. DCAF1's activity has been implicated in cell proliferation and is documented to promote tumorigenesis. Additionally, the DCAF1 WDR domain is hijacked by lentiviral accessory proteins to induce the degradation of host antiviral factors, such as SAMHD1 and UNG2. These diverse roles make DCAF1 an attractive target for therapeutic development in oncology and antiviral strategies. It is also a promising candidate for use in targeted protein degradation. We previously reported a novel ligand, OICR-8268, that targets the DCAF1 WDR domain. In this study, we present the development of OICR-41103, a potent, selective, and cell-active small molecule chemical probe for DCAF1, derived from OICR-8268. The co-crystal structure of the DCAF1-OICR-41103 complex reveals the ligand's binding mode within the WDR central pocket, demonstrating its potential for PROTAC design and development. Notably, OICR-41103 effectively displaces the lentiviral Vpr protein from DCAF1 in both biochemical and cellular settings, highlighting its potential for the development of HIV therapeutics.
人类DCAF1是一种多结构域蛋白，在蛋白质稳态中发挥关键作用。其WD重复结构域作为RING型CRL4和HECT家族EDVP E3泛素连接酶的底物招募模块，能够使特定底物发生泛素化并通过蛋白酶体降解。DCAF1的活性与细胞增殖有关，并有文献记载其可促进肿瘤发生。此外，慢病毒辅助蛋白会劫持DCAF1的WD重复结构域，以诱导宿主抗病毒因子如SAMHD1和UNG2的降解。这些多样的作用使DCAF1成为肿瘤学治疗开发和抗病毒策略中一个有吸引力的靶点。它也是用于靶向蛋白质降解的一个有前景的候选物。我们之前报道了一种靶向DCAF1的WD重复结构域的新型配体OICR-8268。在本研究中，我们展示了OICR-41103的开发过程，它是一种源自OICR-8268的、对DCAF1具有强效、选择性且具有细胞活性的小分子化学探针。DCAF1 - OICR-41103复合物的共晶体结构揭示了配体在WD重复结构域中央口袋内的结合模式，证明了其在PROTAC设计和开发方面的潜力。值得注意的是，在生化和细胞环境中，OICR-41103都能有效地将慢病毒Vpr蛋白从DCAF1上置换下来，突出了其在HIV治疗药物开发方面的潜力。
