Development and crystal structures of a potent second-generation dual degrader of BCL-2 and BCL-xL

Nayak, Digant; Lv, Dongwen; Yuan, Yaxia; Zhang, Peiyi; Hu, Wanyi; Nayak, Anindita; Ruben, Eliza A.; Lv, Zongyang; Sung, Patrick; Hromas, Robert; Zheng, Guangrong; Zhou, Daohong; Olsen, Shaun K.

doi:10.1038/s41467-024-46922-4

Development and crystal structures of a potent second-generation dual degrader of BCL-2 and BCL-xL

Journal Article · Fri Mar 29 00:00:00 EDT 2024 · Nature Communications

DOI:https://doi.org/10.1038/s41467-024-46922-4· OSTI ID:2470117

^[1]; ^[1]; Yuan, Yaxia ^[1]; Zhang, Peiyi ^[2]; Hu, Wanyi ^[2]; Nayak, Anindita ^[1]; Ruben, Eliza A. ^[1]; Lv, Zongyang ^[1]; ^[1]; Hromas, Robert ^[1]; ^[2]; Zhou, Daohong ^[1]; ^[1]

Univ. of Texas Health Science Center at San Antonio, TX (United States)
Univ. of Florida, Gainesville, FL (United States)

Overexpression of BCL-xL and BCL-2 play key roles in tumorigenesis and cancer drug resistance. Advances in PROTAC technology facilitated recent development of the first BCL-xL/BCL-2 dual degrader, 753b, a VHL-based degrader with improved potency and reduced toxicity compared to previous small molecule inhibitors. Here, we determine crystal structures of VHL/753b/BCL-xL and VHL/753b/BCL-2 ternary complexes. The two ternary complexes exhibit markedly different architectures that are accompanied by distinct networks of interactions at the VHL/753b-linker/target interfaces. The importance of these interfacial contacts is validated via functional analysis and informed subsequent rational and structure-guided design focused on the 753b linker and BCL-2/BCL-xL warhead. This results in the design of a degrader, WH244, with enhanced potency to degrade BCL-xL/BCL-2 in cells. Using biophysical assays followed by in cell activities, we are able to explain the enhanced target degradation of BCL-xL/BCL-2 in cells. Most PROTACs are empirically designed and lack structural studies, making it challenging to understand their modes of action and specificity. Our work presents a streamlined approach that combines rational design and structure-based insights backed with cell-based studies to develop effective PROTAC-based cancer therapeutics.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 2470117

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 15; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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