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Discovery of a dual WDR5 and Ikaros PROTAC degrader as an anti-cancer therapeutic

Abstract

WD repeat domain 5 (WDR5), an integral component of the MLL/KMT2A lysine methyltransferase complex, is critically involved in oncogenesis and represents an attractive onco-target. Inhibitors targeting protein-protein interactions (PPIs) between WDR5 and its binding partners, however, do not inhibit all of WDR5-mediated oncogenic functions and exert rather limited antitumor effects. Here, we report a cereblon (CRBN)-recruiting proteolysis targeting chimera (PROTAC) of WDR5, MS40, which selectively degrades WDR5 and the well-established neo-substrates of immunomodulatory drugs (IMiDs):CRBN, the Ikaros zinc finger (IKZF) transcription factors IKZF1 and IKZF3. MS40-induced WDR5 degradation caused disassociation of the MLL/KMT2A complex off chromatin, resulting in decreased H3K4me2. Transcriptomic profiling revealed that targets of both WDR5 and IMiDs:CRBN were significantly repressed by treatment of MS40. In MLL-rearranged leukemias, which exhibit IKZF1 high expression and dependency, co-suppression of WDR5 and Ikaros by MS40 is superior in suppressing oncogenesis to the WDR5 PPI inhibitor, to MS40’s non-PROTAC analog controls (MS40N1 and MS40N2, which do not bind CRBN and WDR5, respectively), and to a matched VHL-based WDR5 PROTAC (MS169, which degrades WDR5 but not Ikaros). MS40 suppressed the growth of primary leukemia patient cells in vitro and patient-derived xenografts in vivo. Thus, dual degradation of WDR5 and Ikaros is a promising anti-cancer strategy.

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Fig. 1: Design of the CRBN-based WDR5 PROTAC MS40 and measurement of MS40 binding to WDR5 and Cereblon (CRBN).
Fig. 2: Mechanism-of-action (MOA) studies of MS40-mediated WDR5 degradation.
Fig. 3: MS40 selectively degrades WDR5 and the CRBN neo-substrates (IKZF1 and IKZF3) in cells.
Fig. 4: MS40 treatment causes a significant loss of the chromatin-bound MLL complex components, concurrent with a decrease of H3K4me2.
Fig. 5: MS40 treatment effectively suppresses the transcription from target genes of WDR5:MLL complexes and IKZF factors.
Fig. 6: Compared to its non-PROTAC analogues (MS40N1 and MS40N2) and a matched WDR5-selective PROTAC (MS169), the WDR5 and IKZF dual degrader MS40 more effectively suppresses the growth of MLL-r acute leukemia cells in vitro.
Fig. 7: MS40 inhibits the growth of primary AML patient cells in vitro and AML PDX in vivo.

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Acknowledgements

We graciously thank Drs. J Bradner, W Kaelin, Y Dou, H Wen, X Shi, and H Jiang for providing reagents and cells used in the study and the Wang and Jin Laboratory members for helpful discussion and technical support. This work was supported in part by the US National Institutes of Health grants R01GM122749 (to JJ), P30CA196521 (to JJ), R01CA211336 (to GGW), R01CA215284 (to GGW), R01CA268384 (to JJ and GGW), R35GM131780 (to AKA), R24GM137786 (to AJT), P20GM121293 (to AJT), R01CA236209 (to AJT), P20GM103429 (to AJT), an NIH/Office of the Director Grant S10OD018445 (to SGM), R01GM137009 (to ZL), U54 CA217297/PRJ001 (to ZL), endowed professorships from the Icahn School of Medicine at Mount Sinai (to JJ and AKA), and grants/awards from Gabrielle’s Angel Foundation for Cancer Research (to GGW), When Everyone Survives (WES) Leukemia Research Foundation (to GGW) and UNC Lineberger Cancer Center UCRF Stimulus Initiative Grants (to GGW and LC). G.G.W. is an American Cancer Society Research Scholar, a Leukemia and Lymphoma Society Scholar, and an American Society of Hematology Scholar in Basic Science. This work utilized the NMR Spectrometer Systems at Mount Sinai acquired with funding from National Institutes of Health SIG grants 1S10OD025132 and 1S10OD028504. We thank UNC’s facilities, including High-throughput Sequencing Facility (HTSF), Bioinformatics Core, Tissue Culture Facility, Animal Studies Core, and UNC Tissue Procurement Facility, for their professional assistance in this work. The cores affiliated with the UNC Cancer Center are supported in part by the UNC Lineberger Comprehensive Cancer Center Core Support Grant P30CA016086.

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DL and XY led biological/genomic and chemical biology studies, respectively, under the guidance of GGW and JJ. JK conducted protein purification and ITC experiments under the supervision of AKA and JJ. AJS, SGM, RDE, and SDB performed mass spectrometry-based proteomics analyses under the supervision of AJT. ZZ and ZL performed GRO-seq and analyzed the data. WG and Y-HT conducted RNA-seq data analysis under the supervision of LC and GGW. HU and DL analyzed the ChIP-seq data. DL, XY, LC, JJ, and GGW analyzed and interpreted experimental data. GGW, JJ, and JL conceived the project. GGW and JJ organized and led the study. DL, XY, JJ, and GGW wrote the manuscript with input from all other authors.

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Correspondence to Jian Jin or Gang Greg Wang.

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JJ, GW, JL, XY, and DL are inventors of a patent application filed by the Icahn School of Medicine at Mount Sinai and University of North Carolina at Chapel Hill. The Jin laboratory received research funds from Celgene Corporation, Levo Therapeutics, Inc., Cullgen, Inc. and Cullinan Oncology, Inc. JJ is a cofounder, scientific advisory board member and equity shareholder in Cullgen, Inc. and a consultant for Cullgen, Inc., EpiCypher, Inc. and Accent Therapeutics, Inc.

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Li, D., Yu, X., Kottur, J. et al. Discovery of a dual WDR5 and Ikaros PROTAC degrader as an anti-cancer therapeutic. Oncogene 41, 3328–3340 (2022). https://doi.org/10.1038/s41388-022-02340-8

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