Regulated induced proximity targeting chimeras—RIPTACs—A heterobifunctional small molecule strategy for cancer selective therapies

• Published in: Cell chemical biology Vol. 31; no. 8; pp. 1490 - 1502.e42
• Main Authors: Raina, Kanak, Forbes, Chris D., Stronk, Rebecca, Rappi, Jonathan P., Eastman, Kyle J., Zaware, Nilesh, Yu, Xinheng, Li, Hao, Bhardwaj, Amit, Gerritz, Samuel W., Forgione, Mia, Hundt, Abigail, King, Madeline P., Posner, Zoe M., Correia, Allison D., McGovern, Andrew, Puleo, David E., Chenard, Rebekka, Mousseau, James J., Vergara, J. Ignacio, Garvin, Ethan, Macaluso, Jennifer, Martin, Michael, Bassoli, Kyle, Jones, Kelli, Garcia, Marco, Howard, Katia, Yaggi, Madeleine, Smith, Levi M., Chen, Jinshan M., Mayfield, Andrew B., De Leon, Cesar A., Hines, John, Kayser-Bricker, Katherine J., Crews, Craig M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 15.08.2024
• Subjects: anticancer drugs; biotechnology; chemical biology; drug discovery; Halda Therapeutics; heterobifunctional molecules; oncology; protein proximity; RIPTAC; ternary complex; biotechnology; drug discovery; chemical biology; Halda Therapeutics; protein proximity; ternary complex; heterobifunctional molecules; RIPTAC; anticancer drugs; oncology
• ISSN: 2451-9456; 2451-9456; 2451-9448
• DOI: 10.1016/j.chembiol.2024.07.005

We describe a protein proximity inducing therapeutic modality called Regulated Induced Proximity Targeting Chimeras or RIPTACs: heterobifunctional small molecules that elicit a stable ternary complex between a target protein (TP) selectively expressed in tumor cells and a pan-expressed protein essential for cell survival. The resulting co-operative protein-protein interaction (PPI) abrogates the function of the essential protein, thus leading to death selectively in cells expressing the TP. This approach leverages differentially expressed intracellular proteins as novel cancer targets, with the advantage of not requiring the target to be a disease driver. In this chemical biology study, we design RIPTACs that incorporate a ligand against a model TP connected via a linker to effector ligands such as JQ1 (BRD4) or BI2536 (PLK1) or CDK inhibitors such as TMX3013 or dinaciclib. RIPTACs accumulate selectively in cells expressing the HaloTag-FKBP target, form co-operative intracellular ternary complexes, and induce an anti-proliferative response in target-expressing cells. [Display omitted] •Heterobifunctional RIPTACs accumulate in cells that express their target protein (TP)•RIPTACs form enduring ternary complexes with TP and essential effector proteins (EP)•The resultant sustained inhibition of the EPs selectively occurs in TP-expressing cells•This strategy can be leveraged to craft new therapeutics to combat diseases (e.g., cancer) Raina et al. present a proof-of-concept approach to modulate protein-protein interaction (PPI) with heterobifunctional regulated induced proximity targeting chimeras (RIPTACs) that induce an enduring interaction between target proteins (TPs) and effector proteins (EPs). The RIPTACs arrest cancer cell growth by selectively inhibiting a pan-essential effector protein in ternary complex with target proteins expressed at elevated levels in cancer cells.