Presentation at AACR highlights the “hold and kill” mechanism of RIPTAC therapeutics in prostate cancer models including clinically relevant androgen receptor mutants

Halda has a pipeline of orally-available RIPTAC therapeutics which are heterobifunctional small molecules designed to treat cancer selectively and overcome common drug resistance

NEW HAVEN, CT, USA I April 17, 2023 IHalda Therapeutics, a biotechnology company developing a novel class of cancer therapies called RIPTACTM (Regulated Induced Proximity TArgeting Chimeras) therapeutics, today announced a poster presentation for its lead RIPTAC therapeutic program for prostate cancer at the annual meeting of the American Association for Cancer Research (AACR) being held in Orlando, Florida, from April 14-19, 2023. The preclinical data showed oral efficacy of the RIPTAC therapeutics as a monotherapy and demonstrated anti-tumor activity superior to the standard of care agent in prostate cancer, enzalutamide. Combination therapy with PARP inhibitors is also being explored and RIPTAC therapeutics may have a complementary mechanism.

“Our presentation at AACR is an exciting opportunity to share the growing body of evidence demonstrating the anti-tumor efficacy of the “hold and kill” mechanism of RIPTAC therapeutics which can be applied to address cancers in early or later-line therapy,” said Kat Kayser-Bricker, PhD, Chief Scientific Officer of Halda Therapeutics. “These preclinical efficacy results of RIPTAC therapeutics targeting prostate cancer highlight the promise of a novel approach to overcome bypass mechanisms of resistance that evolve during cancer therapy, which is a common limitation of today’s precision oncology medicines.”

The preclinical data describe the anti-tumor activity of prostate cancer RIPTAC therapeutics, novel orally bioavailable heterobifunctional small molecules, that use a unique “hold and kill” mechanism resulting in selective cancer cell killing by bringing together two proteins: the tumor-specific protein androgen receptor (AR) and an essential protein involved in transcription regulation. A trimeric complex is formed by the prostate cancer RIPTAC therapeutic and the two proteins which drives the formation of new protein-protein interactions; the resultant trimeric species thereby abrogates the function of the essential protein within AR-expressing prostate cancer cells, leading to selective cancer cell death.

The poster presentation, with lead author Xinheng Yu, PhD, Research Investigator at Halda, is entitled “Prostate Cancer RIPTACTM Therapeutics Demonstrate Activity in Preclinical Models of Enzalutamide-Resistant Prostate Cancer,” and includes the following results:

  • In prostate cancer cells, the RIPTAC therapeutics demonstrated the formation of trimeric complexes with AR (and clinically relevant AR mutants) and a protein with essential function involved in transcription regulation.
  • In castrated mice bearing VCaP xenografts, multiple RIPTAC therapeutics demonstrated superior oral efficacy in vivo compared with enzalutamide, the current standard of care agent for prostate cancer.
  • RIPTAC therapeutics targeting prostate cancer downregulated genes involved in homologous recombination repair, inducing BRCAness. PARP inhibitors can induce synthetic lethality under these conditions, and combination therapy will be explored.
  • The design of the RIPTAC therapeutics targeting prostate cancer achieved desired anti-tumor activity and pharmacology through optimized trimeric complex formation, AR-selective cell killing, and oral bioavailability.

The poster presentation can be found on Halda’s website here.

About Prostate Cancer and mCRPC

Prostate cancer is the most common non-skin cancer in men. In the U.S., 1 in 8 men will be diagnosed with prostate cancer in his lifetime.1 Prostate cancer depends on the androgen receptor (AR), a transcription factor critical for prostate cancer growth and progression. Treatment initially relies on androgen deprivation therapy, as well as AR signaling inhibitors (ARSIs). However, resistance to antiandrogen interventions eventually emerges, and is driven by many heterogenous bypass mechanisms including genomic alterations in AR. The long-term prognosis for patients with metastatic castration resistant prostate cancer (mCRPC) is poor, with a relatively short overall survival. In the mCRPC form of the disease, more than 80% of patients harbor amplifications of the AR gene or the upstream enhancer region of DNA.2 AR remains expressed in tumors even if they are no longer AR dependent, dramatically reducing effectiveness of ARSIs, thus representing a vast unmet need.

About Halda Therapeutics

Halda Therapeutics is a biotechnology company founded by Professor Craig Crews from Yale University developing a proprietary RIPTAC™ (Regulated Induced Proximity TArgeting Chimeras) modality that works by a novel “hold and kill” mechanism for the precision treatment of cancer. The novel mechanism of action of RIPTAC therapeutics is uniquely designed to address cancer’s ability to evolve bypass mechanisms of resistance, a common limitation of today’s precision oncology medicines. The company has built a robust pipeline of novel mechanism of action therapeutics, with an initial focus on bringing new drugs to address these difficult to treat patient populations. Our leading programs are in major solid tumor types, with additional RIPTAC therapeutic programs in development to treat unmet medical needs in oncology. Halda is led by a leadership team with deep expertise in bifunctional drug discovery, platform innovation, and company building, and is located in New Haven, CT. For more information, please visit and follow us on Twitter and LinkedIn.

1Cancer Stat Facts: Prostate Cancer, Surveillance, Epidemiology and End Results (SEER) Database, National Cancer Institute.

2 Quigley, D.A., et al., Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer, Cell, 174(3), 2018 July 26.

SOURCE: Halda Therapeutics