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

  • Cell Chem Biol. 2024 Aug 15;31(8):1490-1502.e42. doi: 10.1016/j.chembiol.2024.07.005.
Kanak Raina  1 ,  Chris D Forbes  1 ,  Rebecca Stronk  1 ,  Jonathan P Rappi Jr  1 ,  Kyle J Eastman  1 ,  Nilesh Zaware  1 ,  Xinheng Yu  1 ,  Hao Li  1 ,  Amit Bhardwaj  1 ,  Samuel W Gerritz  1 ,  Mia Forgione  1 ,  Abigail Hundt  1 ,  Madeline P King  1 ,  Zoe M Posner  1 ,  Allison D Correia  1 ,  Andrew McGovern  1 ,  David E Puleo  1 ,  Rebekka Chenard  1 ,  James J Mousseau  1 ,  J Ignacio Vergara  2 ,  Ethan Garvin  1 ,  Jennifer Macaluso  1 ,  Michael Martin  1 ,  Kyle Bassoli  1 ,  Kelli Jones  1 ,  Marco Garcia  1 ,  Katia Howard  1 ,  Madeleine Yaggi  1 ,  Levi M Smith  1 ,  Jinshan M Chen  1 ,  Andrew B Mayfield  2 ,  Cesar A De Leon  2 ,  John Hines  2 ,  Katherine J Kayser-Bricker  3 ,  Craig M Crews  4
Affiliations
  • 1. Halda Therapeutics OpCo Inc, New Haven, CT, USA.
  • 2. Department of Molecular, Cellular, & Developmental Biology, Yale University, New Haven, CT, USA.
  • 3. Halda Therapeutics OpCo Inc, New Haven, CT, USA. Electronic address: [email protected].
  • 4. Department of Molecular, Cellular, & Developmental Biology, Yale University, New Haven, CT, USA; Department of Pharmacology, Yale University, New Haven, CT, USA; Department of Chemistry, Yale University, New Haven, CT, USA. Electronic address: [email protected].
PMID: 39116881 DOI: 10.1016/j.chembiol.2024.07.005
Abstract

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.

Keywords
Halda Therapeutics; RIPTAC; anticancer drugs; biotechnology; chemical biology; drug discovery; heterobifunctional molecules; oncology; protein proximity; ternary complex.
Products