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

Kanak Raina, Chris D. Forbes, Rebecca Stronk, Jonathan P. Rappi, Kyle J. Eastman, Nilesh Zaware, Xinheng Yu, Hao Li, Amit Bhardwaj, Samuel W. Gerritz, Mia Forgione, Abigail Hundt, Madeline P. King, Zoe M. Posner, Allison D. Correia, Andrew McGovern, David E. Puleo, Rebekka Chenard, James J. Mousseau, J. Ignacio VergaraEthan Garvin, Jennifer Macaluso, Michael Martin, Kyle Bassoli, Kelli Jones, Marco Garcia, Katia Howard, Madeleine Yaggi, Levi M. Smith, Jinshan M. Chen, Andrew B. Mayfield, Cesar A. De Leon, John Hines, Katherine J. Kayser-Bricker, Craig M. Crews

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

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.

Original languageEnglish
Pages (from-to)1490-1502.e42
JournalCell Chemical Biology
Volume31
Issue number8
DOIs
StatePublished - 15 Aug 2024
Externally publishedYes

Keywords

  • Halda Therapeutics
  • RIPTAC
  • anticancer drugs
  • biotechnology
  • chemical biology
  • drug discovery
  • heterobifunctional molecules
  • oncology
  • protein proximity
  • ternary complex

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