Daohong Zhou, M.D., a professor of pharmacodynamics and the Henry E. Innes Professor of Cancer Research, and Guangrong Zheng, Ph.D., an associate professor of medicinal chemistry, were awarded the UF College of Pharmacy’s “Outstanding Publication in Basic Sciences Research Award.”
The “Outstanding Publication in Basic Sciences Research Award” recognizes significant faculty research and clinical contributions having major impacts and/or innovations in approach in basic sciences, clinical sciences and in teaching or clinical practice.
The article published in Nature Medicine is about the discovery of DT2216, a proteolysis-targeting chimera (PROTAC) that can potently and specifically degrade BCL-XL, and evaluation of its potential in treating leukemia, lymphoma, breast cancer, and small cell lung cancer. BCL-XL is a well validated and highly valued cancer target due to its high expression in solid tumors and some leukemias and its significant contribution to cancer resistance to chemo- and targeted-therapy. However, BCL-XL has been considered “undruggable” or “difficult-to -drug” after many years of research and development of drugs that can directly inhibit BCL-XL. The reason is that platelets are solely dependent on BCL-XL for survival. BCL-XL inhibitors cause severe thrombocytopenia, the more effective of targeting cancer cells, the more toxic to platelets.
In this paper, Zhou and Guangrong Zheng, Ph.D., an associate professor of medicinal chemistry, and their research team report an innovative strategy to minimize the on-target platelet toxicity associated with BCL-XL inhibition. Instead of inhibiting the function of BCL-XL, the solution is to design PROTAC molecules to specifically degrade this protein. PROTACs were designed with a BCL-XL–binding moiety connected via an optimized linker to a ligand of the von Hippel-Lindau (VHL) E3 ligase, which is poorly expressed in platelets. Because PROTACs rely on E3 ligases to induce protein degradation, Zhou and Zheng were able to show that the BCL-XL-targeting PROTACs do not induce BCL-XL degradation in platelets and thus has minimum toxicity on platelets both in vitro and in vivo. They also demonstrated in many cell line–derived or patient-derived xenograft mouse models that the lead BCL-XL PROTAC, DT2216, can suppress growth of several tumors, including T-cell acute lymphoblastic leukemia (T-ALL), drug-resistant breast cancer, and small cell lung cancers, as a single agent or in combination with other drugs. The antitumor efficacy of DT2216 was associated with its ability to induce degradation of BCL-XL, consistent with the notion that DT2216 acts as a BCL-XL–specific PROTAC in vivo.
Overall, Zhou and Zheng were able to “rescue” BCL-XL as a high value cancer target through the innovative PROTAC approach. Their findings support DT2216 to be developed as a first-in-class BCL-XL-targeting antitumor agent. This is also the first example in the PROTAC field that this technology can be potentially used to achieve tissue/cell type selectivity. This paper was highlighted by Cancer Discovery (https://cancerdiscovery.aacrjournals.org/content/candisc/10/2/174.1.full.pdf), one of the top journals in cancer research, and has already been cited 5 times since its publication at the end of December 2019.