kt-4000 series / Rakovina Therap - LARVOL DELTA

Rakovina Therapeutics Presents Preclinical Data Supporting Potential Broad Anticancer Activity of kt-4000 Series at the American Association of Cancer Research (AACR) Annual General Meeting (GlobeNewswire) - "The data presented demonstrate that, following treatment, representative kt-4000 series drug candidates release an alkylating agent resulting in increased expression of γH2AX, a DNA damage marker, in cancer cells. kt-4000 drug candidates simultaneously exhibit potent PARP inhibition at low nanomolar concentrations. The combined effect leads to G2/M cell cycle arrest and cell death in HR-proficient cancer cells, normally resistant to PARP inhibitor treatment."

Preclinical • Oncology

Evaluation of a novel class of bifunctional DNA alkylating agent and PARP inhibitor (AACR 2022) - "Detection of pH2AX by western blot and immunofluorescence assays was done using anti-phospho histone H2AX (Ser139) antibody from Cell Signaling Technologies. kt-4000 series compounds are potent inhibitors of both PARP1 and PARP2 with IC50 values in the low nM range, comparable to FDA-approved PARP inhibitors. The compounds release methylator in a similar manner as temozolomide, an FDA-approved DNA alkylating agent... Our novel class of PARP inhibitors combined with DNA alkylating function show potent inhibition of both PARP1 and PARP2. These compounds also lead to accumulation of H2AX phosphorylation, a sensitive marker for double-strand breaks, and S-phase and G2/M cell cycle arrest. Development of these bifunctional, single molecule therapies may extend the clinical utility of PARP inhibitors to DDR proficient disease and increase efficacy for DDR deficient disease."

Oncology • BRCA1 • BRCA2 • PARP2