Selective PARP1 inhibitor(Acerand Therapeutics)

We evaluated the activity of AZD8205, a B7-H4–directed antibody–drug conjugate (ADC) bearing a novel topoisomerase I inhibitor (TOP1i) payload, alone and in combination with the PARP1-selective inhibitor AZD5305, in preclinical models.

IHC and deep-learning–based image analysis algorithms were used to assess prevalence and intratumoral heterogeneity of B7-H4 expression in human tumors. Several TOP1i-ADCs, prepared with Val-Ala or Gly–Gly–Phe–Gly peptide linkers, with or without a PEG8 spacer, were compared in biophysical, in vivo efficacy, and rat toxicology studies. AZD8205 mechanism of action and efficacy studies were conducted in human cancer cell line and patient-derived xenograft (PDX) models.

Evaluation of IHC-staining density on a per-cell basis revealed a range of heterogeneous B7-H4 expression across patient tumors. This informed selection of bystander-capable Val-Ala–PEG8–TOP1i payload AZ14170133 and development of AZD8205, which demonstrated improved stability, efficacy, and safety compared with other linker–payload ADCs. In a study of 26 PDX tumors, single administration of 3.5 mg/kg AZD8205 provided a 69% overall response rate, according to modified RECIST criteria, which correlated with homologous recombination repair (HRR) deficiency (HRD) and elevated levels of B7-H4 in HRR-proficient models. Addition of AZD5305 sensitized very low B7-H4–expressing tumors to AZD8205 treatment, independent of HRD status and in models representing clinically relevant mechanisms of PARPi resistance.

These data provide evidence for the potential utility of AZD8205 for treatment of B7-H4–expressing tumors and support the rationale for an ongoing phase 1 clinical study (NCT05123482).See related commentary by Pommier and Thomas, p. 991

Inhibition of poly (ADP-ribose) polymerase (PARP) has been applied with great success in the clinical treatment of homologous recombination-deficient malignancy. Recent study demonstrated that not only PARP-1 inhibition but also DNA trapping contributes to the efficacy in BRCA mutant tumors and the toxicities results from the poor selectivity of PARP-1 over PARP-2 as well as their DNA trapping. Herein, a series of 3-ethyl-1,5-naphthyridin-2(1H)-one derivatives (7a-7l, 8a-8n) were synthesized and identified as PARP-1 selective inhibitors and PARP-1 DNA trappers. Among them, compound 8m was found to be highly potent and selective. It inhibited PARP-1 activity and BRCA mutant DLD-1 cell activity with IC₅₀ values of 0.49 nM and 4.82 nM, and the in vitro DNA trapping efficacy of compound 8m was 1.85 nM. Compared with AZD5305, compound 8m significantly improved the selectivity of PARP-1 over PARP-2 as well. Compound 8m was>1000-fold selective for PARP-1 DNA trapping over PARP-2.