A new class of oral drugs is being designed to block an enzyme called tankyrase 1, which could offer a treatment option for aggressive breast cancers that currently have few therapies. Breast cancer subtypes with poor prognosis—such as triple-negative or BRCA-mutant tumours—often lack targeted treatments. Tankyrase 1 helps cancer cells survive by stabilising proteins that drive tumour growth and repair DNA damage. Inhibiting this enzyme exploits a vulnerability unique to these cancer cells, a strategy called synthetic lethality. The research team has already identified prototype inhibitors using computer-based screening and now aims to refine them into orally-bioavailable drugs suitable for human trials. If successful, these drugs would enter first-in-class Phase 1 clinical trials at The Royal Marsden Hospital. The programme also includes developing companion biomarkers—tests that identify which patients are most likely to benefit—and using crystal structures of the active enzyme to guide drug design. This could lead to a new treatment pathway for patients with limited options, though the drugs are still years from routine use. The work is primarily applied drug development, building on fundamental discoveries about tankyrase biology and cancer cell vulnerabilities.
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We propose to develop orally-bioavailable small molecule drugs that inhibit tankyrase 1 - a novel target for breast cancer therapy. Our data indicate that such drugs could be used in a synthetic lethality approach to treat cancer. A tankyrase 1 inhibitor would confront several tumour-specific characteristics and would be useful for treatment of specific breast cancer subtypes with a poor prognosis, where few treatment options exist. As part of this drug research programme, we will build on our existing in-house and proprietary knowledge to generate novel, patented candidate drugs that will be used in first in class Phase 1 clinical trials at The Royal Marsden Hospital. The programme we propose will include: 1) the further development of our existing prototype tankyrase 1 inhibitors, which we have identified following pre-selection of a compound set using an in silico based screen, 2) the delineation of a proprietary crystal structure of the active form of tankyrase 1 to guide the design of inhibitors, 3) a comprehensive medicinal chemistry programme, 4) the use of cellular assay systems and in vivo therapeutic efficacy assessments to aid the development of inhibitors and companion biomarkers and 5) high-throughput genetic and drug synergy screens that will identify companion biomarkers and direct the design of clinical trials. This programme will be underpinned by: (i) the unique in-depth knowledge of breast cancer, synthetic lethality and tankyrase 1 biology of the research team led by the Principal Applicant, (ii) the strong track-record of key members of the project team in drug research, and (iii) the strengths in structural biology and drug development available within the host Institute.
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