On August 7, 2024 Halda Therapeutics, a biotechnology company developing a novel class of cancer therapies called RIPTACTM (Regulated Induced Proximity TArgeting Chimeras) therapeutics, reported the publication of data demonstrating proof-of-mechanism and pharmacology of a RIPTAC therapeutic, published in the peer-reviewed journal Cell Chemical Biology (Press release, Halda Therapeutics, AUG 7, 2024, View Source [SID1234645520]). The manuscript entitled, "Regulated Induced Proximity Targeting Chimeras (RIPTACs): a Heterobifunctional Small Molecule Strategy for Cancer Selective Therapies," describes the creation of a chemical biology model of RIPTAC therapeutics and illustrates the mechanism of action of this novel drug modality to enable selective killing of cancer cells.

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RIPTAC therapeutics are heterobifunctional small molecules that work by a novel "hold and kill" mechanism, bringing together two proteins, a tumor-specific protein and a protein with essential function, resulting in abrogation of the essential cell function, and subsequently, cancer cell death. This unique pharmacology does not require the target protein to be the driver of the cancer, unlike the majority of precision oncology medicines that rely on an oncogene driver as the target protein. In addition, the novel mode of action of RIPTAC therapeutics is designed to overcome the known bypass mechanisms of resistance that evolve during a course of therapy, a common limitation of today’s precision oncology medicines, thereby opening the potential for their use in both late and early stages of cancer treatment.

"We are excited to share data demonstrating the mechanism of action of RIPTAC molecules, as well as how the protein proximity paradigm can be extended into direct cancer cell killing," said Kanak Raina, PhD, lead author and Head of Biology at Halda. "Insights gained from the detailed interrogation of this chemical biology model have provided Halda with a robust foundation that has resulted in our pipeline of RIPTAC therapeutics for major cancers."

The publication details several chemical biology approaches using a model with a HaloTag‑FKBP target protein to dissect the mechanism of action and pharmacology of RIPTAC molecules. Key findings from the study include:

RIPTAC therapeutics demonstrated selective anti-proliferative activity in cells expressing the target protein.
A ternary complex formed by the target protein, the RIPTAC molecule, and a pan-essential protein abrogated the function of the essential protein selectively in target-expressing cells, causing cell death.
Several different pan-essential cellular proteins were shown to be amenable for selective cancer cell killing when incorporated into RIPTAC ternary complexes.
Halda’s scientific founder, Craig Crews, PhD, Professor of Molecular, Cellular, and Developmental Biology at Yale University, is an author on the paper in Cell Chemical Biology and is a pioneer of induced proximity biology that has led to the vision and invention of heterobifunctional drugs. Professor Crews commented, "RIPTAC therapeutics address a shortcoming shared by most current precision medicines for cancer, namely, the reliance on oncogenic driver proteins which can result in drug resistance in a large percentage of patients. The RIPTAC modality offers a new oral, selective, and widely applicable cancer cell-killing mechanism that can overcome drug resistance and can be used in advanced cancer where resistance has emerged, as well as in early stage disease where the tumor-specific protein is expressed."