Breakpoint Therapeutics Announces Development Candidate Nomination and Start of IND-Enabling Activities of Potential Best-in-Class Polymerase Theta (Pol θ / POLQ) Inhibitor

  • Breakpoint’s polymerase theta inhibitor development candidate, a potent and selective small molecule, was nominated based on its best-in-class potential to treat cancers with defined defects in DDR pathways
  • Excellent profile of Breakpoint’s polymerase theta inhibitor provides mechanistic synergy and huge optionality for clinical combination with various other agents, including targeted drugs such as PARP inhibitors, chemo- and radiation therapy, radioligand therapy (RLT) and ADCs
  • Candidate molecule originated from integrated drug discovery efforts performed in alliance with Evotec


Hamburg, Germany, 21 March 2024
Breakpoint Therapeutics GmbH (“Breakpoint”), a company dedicated to the discovery and development of drugs targeting the DNA Damage Response (DDR), announced today that it has nominated its first preclinical development candidate, BTX-011, an inhibitor of polymerase theta (Pol θ / POLQ) with best-in-class potential, for the treatment of solid tumours. IND-enabling activities have already commenced.

BTX-011 is an oral, highly potent and selective inhibitor of DNA polymerase theta that shows strong and durable in vivo efficacy in relevant cancer models when combined with standard of care PARP inhibitors. Tumour-specific potentiation of drug efficacy is achieved without adding toxicity or detrimental side effects on normal cells. Combining existing therapies with BTX-011 could deliver superior and synergistic tumour cell killing and inhibit the development of therapy resistance. BTX­­­-011 therefore could transform outcomes for cancer patients, through improving the efficacy and duration of therapy response, and providing a potentially curative treatment.

This potential best-in-class preclinical candidate was discovered leveraging Evotec’s fully integrated small molecule drug discovery and development platform. Breakpoint holds all development and commercial rights to the compound.

Dr Daniel Speidel, Managing Director of Breakpoint Therapeutics, commented: “We are proud to announce this important milestone for the company as we deliver the first preclinical development candidate molecule from Breakpoint’s DDR pipeline. From the beginning, Breakpoint’s commitment has been to select only molecules with best-in-class profile and a clear potential to be transformative for cancer therapy. Our polymerase theta inhibitor has these properties, and we look forward to progressing it into the clinic to deliver benefit to patients.”

Dr Jonathan Hollick, Managing Director and Head of Research, added: “The nomination of BTX-011 as our first DDR candidate drug is the result of a comprehensive drug discovery effort executed in close collaboration with Evotec. By leveraging our expertise in drugging challenging targets and a suite of technologies within Evotec’s integrated drug discovery framework, we have optimised multiple chemical series, each with different modes of action against pol theta, to select compounds that we believe have unparalleled development potential. Based on the strong, durable antitumour efficacy that BTX-011 has displayed in preclinical cancer models, we are excited to take this step towards the clinic where we can tackle the challenge of therapy resistance in oncology.”

Dr Cord Dohrmann, Chief Scientific Officer of Evotec and Advisory Board Member of Breakpoint Therapeutics, commented: “We are very excited to celebrate this milestone, together, with Breakpoint Therapeutics. Since the formation of Breakpoint Therapeutics, there has been strong collaboration to advance early projects through discovery and pre-clinical development. This milestone, marking the progression from target ID to a preclinical development candidate molecule, validates Evotec’s spin-out and virtual operations model. It highlights that the creation aligns well with our strategy of generating upside with an optimal risk-reward profile, advancing highly capital-efficient virtual biotech initiatives with the mission to develop first- and best-in-class drugs, for patients.”

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About DNA polymerase theta

DNA polymerase theta (Pol θ / POLQ) is a multifunctional enzyme with polymerase and ATPase-driven helicase domains. Both Pol θ domains have functional relevance in DNA repair processes, especially the microhomology-mediated end-joining (MMEJ) repair pathway which cancer cells rely on to survive in some contexts, such as tumour-specific BRCA deficiency. Polymerase theta expression is largely absent in normal cells; however, it is upregulated in multiple cancers where expression correlates with poor prognosis and therapy resistance. This suggests a wide therapeutic window for DNA polymerase theta inhibitors.

About Breakpoint Therapeutics

Breakpoint Therapeutics is developing targeted cancer therapies that modulate DNA damage response (DDR) pathways. Through precise interference with DNA repair, our drug candidates are designed to kill cancer cells without harming healthy cells. We leverage new insights and the concept of synthetic lethality to increase the therapeutic window and achieve better outcomes for patients with therapy-resistant and hard-to-treat cancers.

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Media contact:

Dr Daniel Speidel, Managing Director,