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Recently, Professor Craig M. Crews, in association with upstart company Halda Therapeutics, demonstrated a novel cancer therapy called Regulated Induced Proximity Targeting Chimeras (RIPTAC) that promises to overcome cancer drug resistance and bring a new option for oncology treatment.

Targeted Protein Degradation

Professor Crews is a pioneer in the field of targeted protein degradation with proteolysis targeting chimera (PROTAC), a heterobifunctional molecule first reported in 2001, where PROTAC One end can bind to the target protein and the other end binds to the E3 ubiquitin ligase. PROTAC drives target proteins close enough to E3 ubiquitin ligase and catalyzes them polyubiquitination so that they are recognized and degraded by the cell's proteasome system.

Several targeted therapies, including protein degradation therapies, are based on targeting oncogenic driver proteins that promote tumor cell survival and proliferation because of mutations or overexpression. By inhibiting the activity of these drivers or degrading them, cancer cells can be killed. However, targeting cancer drivers is one of the factors that promote cancer drug resistance. Cancer cells can develop resistance to targeted therapies by creating mutations or activating other signaling pathways so that they are no longer dependent on the function of the target protein.

Although tumor cells become resistant to targeted therapies, these target proteins are still highly expressed in cancer cells, such as high levels of androgen receptors in resistant prostate cancer cells. Therefore, the development of new cancer therapies using these proteins, which are specifically highly expressed in cancer cells, may be a promising strategy.

Why RIPTAC?

Regulated induced proximity targeting chimera (RIPTAC) is a new model of heterogeneous bifunctional molecules, consisting of three parts: two protein-targeting ligands and a linker connecting the two ligands, one of which binds to a protein highly expressed in tumor cells and the other to a protein intracellularly closely related to cell survival.

RIPTAC works through a novel "hold and kill" mechanism that combines two proteins, a cancer-specific protein and protein with essential functions, to form a tumor-specific protein-RIPTAC-essential protein ternary complex inhibits the activity of the essential protein, thereby inducing tumor cell death. In contrast, normal cells are not killed by RIPTAC molecules because they do not express high levels of cancer-specific proteins and cannot form the ternary complexes required for the activity of RIPTAC. RIPTAC addresses a common drawback of most current targeted drugs because it does not rely on the cancer-driven function of the target protein.

Fig. 1 RIPTACs selectively inhibit the proliferation of cells expressing target proteins (Raina, 2023)

Design of RIPTAC

• Algorithm: An algorithms is used to select complementary pairs from hundreds of tumor-specific proteins and proteins with essential functions.
• Ligand and linker: Two protein-targeting ligands and a linker are the three key components of RIPTAC. Structure-based drug design and expertise of bifunctional molecular design and synthesis are applied to ensure that RIPTAC drives the formation of protein-protein interactions and selective cell death.
• In vitro/In vivo analysis: Assesses the kinetics of tumor-specific protein-RIPTAC-essential protein ternary complex formation, as well as the pharmacodynamics of RIPTAC by in vitro/in vivo analysis.

Current Advances in RIPTAC

In January, Professor Crews' team described a proof-of-concept for RIPTAC. In this study, a series of bifunctional molecules were designed and developed that bind to recombinant proteins highly expressed in cell lines at one end and to different intracellular proteins that maintain cell survival, including BET, PLK1, CDK, and others, at the other end. Experimental results show that these molecules significantly inhibit cell proliferation in cell lines highly expressing recombinant proteins, providing a proof-of-concept for the mechanism of action of RIPTAC molecules in selectively killing cancer cells.

In February, Halda Therapeutics unveils its first pipeline data for RIPTAC™ therapeutics at the 2023 ASCO Genitourinary Cancers Symposium. The RIPTAC targeting the androgen receptor (AR) is expected to be used to overcome drug resistance in patients with metastatic castration-resistant prostate cancer (mCRPC). AR is a driver of prostate cancer, but prolonged dosing leads to resistance brought about by factors such as mutations in the AR genome, which is abundantly expressed in mCRPC but is no longer a driver of the tumor. Preclinical data showed that this RIPTAC specifically delivers the drug to the tumor tissue by recognizing the AR, which subsequently forms a ternary complex with the AR and essential proteins involved in transcriptional regulation, ultimately leading to the death of the prostate cancer cell line. In animal models, this RIPTAC has good oral bioavailability and tumor suppressive activity.

Reference

1. Raina, K., et al. Regulated Induced Proximity Targeting Chimeras (RIPTACs): a Novel Heterobifunctional Small Molecule Therapeutic Strategy for Killing Cancer Cells Selectively, bioRxiv, 2023.