Development of inhibitors targeting Plk1 polo-box domain

Division Of Basic Sciences - Nci

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Abstract

We have been developing a new class of inhibitors (as opposed to ATP-competitive inhibitors) against the Plk1 PBD. Due to the distinct binding nature of protein-protein interaction inhibitors, PBD inhibitors are expected to exhibit a high level of specificity. Notably, the two most advanced ATP analog inhibitors against Plk1, volasertib/BI6727 and GSK461364A, performed poorly in clinical trials because of their less-than-acceptable tolerability. Thus, PBD inhibitors could serve as a valuable alternative for anti-Plk1 therapy. Based on the high-affinity interaction between the Plk1 PBD and PBIP1 that we isolated as a Plk1-specific target, I developed a collaborative drug discovery project funded by the NCI CCR (FLEX Synergy Award: 4/1/2017-9/30/21) by recruiting four other intramural research groups (Dr. Ken Jacobson, NIDDK, Dr. Ganesha Bantukallu, National Center for Advancing Translational Sciences [NCATS], Dr. Frank Gonzalez, NCI, and Dr. Beverly Mock, NCI). My group played a central role in this collaboration by conducting primary fluorescence polarization-based high-throughput screening (collaborated with NCATS, NIH, to screen >0.5 million small molecules), secondary ELISA-based assays to confirm the activity and eliminate false positives, and various cell-based inhibition assays to test cellular efficacies. We also coordinated multilateral efforts to perform pre-clinical drug metabolism and pharmacokinetics (Dr. Gonzalez), medicinal hit-to-lead optimization (Dr. Jacobson), and mouse xenograft tumor assays (Dr. Mock). Chemical synthesis and X-ray crystallography were performed by two FLEX fellows (Drs. Celeste N. Alverez and Yaozong Chen) and later a Predoctoral/Visiting Fellow (Dr. Klara Kirsch). This work resulted in three multi-collaboration papers (Alverez, CN et al., 2020, J. Med. Chem.; Park, JE et al., 2023, ACS Pharm. and Trans. Sci.; Park, JE et al., 2023, PNAS), a U.S. patent (No. 18/028,463 filed on March 24, 2023, following an international patent application [No. PCT/US2021/052054] filed on September 24, 2021), and a US provisional patent (Application number: No. 63/455,608; filed on March 30, 2023) covering the latest inhibitor, called Allopole. I believe this project has been an exemplar of multilateral collaborations within the NIH.