brca-1-in-1

BRCA1-IN-1 is a novel small-molecule-like inhibitor of BRCA1 with an IC50 of 0.53 μM and a Ki of 0.71 μM.

BRCA1-IN-2 is a cell membrane-crossing BRCA1 protein-protein interaction (PPI) inhibitor with antitumor activity that acts by disrupting the interaction of BRCA1 (BRCT)2 with proteins.

PARP1-IN-27 (Compound 9B) serves as an inhibitor of both PARP1 and PARP2, exhibiting IC 50 values of 2.53 nM and 6.45 nM, respectively, in SUM149PT cells. This compound effectively suppresses the proliferation of BRCA-mutated cancer cell lines such as SUM149PT, HCC1937, and Capan-1, with respective IC 50 values of 0.62, 1.91, and 4.26 μM. Additionally, PARP1-IN-27 exacerbates DNA double-strand breaks, enhances ROS production, causes G2/M phase cell cycle arrest, and triggers apoptosis in SUM149PT cells.

USP1-IN-11 (compound 38-P2) is a selective, reversible, and non-competitive inhibitor of USP1 (Ubiquitin-specific protease 1). It activates the DDR (DNA damage repair) pathway, leading to cell cycle arrest and apoptosis, thereby inhibiting cell survival. USP1-IN-11 increases sensitivity to Olaparib in drug-resistant cells and works synergistically with Andrographolide in cancer cells with functional BRCA. In the MDA-MB-436 xenograft model, USP1-IN-11 demonstrates significant dose-dependent antitumor activity.

USP1-IN-11 (compound 38-P2) is a selective, reversible, and non-competitive inhibitor of USP1 (Ubiquitin-specific protease 1). It promotes the activation of the DDR (DNA damage repair) pathway, inducing cell cycle arrest and apoptosis, thereby inhibiting cell viability. USP1-IN-11 increases the sensitivity of cells resistant to Olaparib and shows synergistic effects with Andrographolide in cancer cells with normal BRCA function. In the MDA-MB-436 xenograft model, USP1-IN-11 exhibits a significant dose-dependent antitumor effect.

PARP1-IN-37 (Compound 8) is an orally active and selective inhibitor of poly (ADP-ribose) polymerases 1 and 2 (PARP1/2), with an IC50 value of 24 nM for PARP1. It inhibits PARP activity in cells with an EC50 value of 3.7 μM and holds potential for research on BRCA-mutated tumors, such as breast and ovarian cancers.

EXO1-IN-1 (Compound F684) is a potent and selective inhibitor of exonuclease 1 (EXO1) with an IC50 of 15.7 μM. It inhibits DNA end resection, promotes the accumulation of DNA double-strand breaks, and induces S-phase polyadenylation, thereby disrupting DNA repair pathways in homologous recombination-deficient (HRD) cancer cells. This selectivity effectively targets and kills tumor cells with homologous recombination gene defects, such as BRCA1/2 mutations. EXO1-IN-1 holds promise for researching cancers with homologous recombination deficiencies, including BRCA-related tumors.

PARP/EZH2-IN-1 is a novel dual inhibitor targeting PARP (IC50 6.87 nM) and EZH2 (IC50 36.51 nM), showing promising potential for treating triple-negative breast cancer with wild-type BRCA.

JPI 547, also known as NOV 1402, is an oral inhibitor of PARP 1/2 and Tankyrase 1/2. JPI-547 demonstrated anti-tumor activity in BRCA-deficient xenograft models as a single-agent and in combination with chemotherapy and immune checkpoint inhibitors.

SC10914 is a highly potent PARP inhibitor (PARP1 IC50 = 7.87 nM) with potent anti-proliferative activity against human BRCA deficient tumor cells (MDA-MB-436, BRCA1 deficient, IC50 = 4.03 nM, Capan-1 BRCA2 deficient, IC50 = 11.66 nM) and PTEN deficient tumor cells (HGC-27,PTEN deficient, IC50 = 0.35 μM). SC10914 showed potent anti-tumor activity in BRCA1/2 mutant tumor models and better pharmacokinetics profile has the potential to be selected as the clinical candidate for the treatment of treatment of BRCA1/2 deficient cancers.

VEGFR/PARP-IN-1 (Compound 14b) is a dual inhibitor of VEGFR and PARP with IC50 values of 191 nM and 60.9 nM, respectively. It impairs DNA damage repair pathways, promotes apoptosis, and halts cells in the G2/M phase. This compound demonstrates considerable antiproliferative activity against BRCA wild-type breast cancer cells, with IC50 values of 4.1 μM for MDA-MB-231 cells and 3.5 μM for MCF-7 cells, indicating its potential as an antitumor and anti-metastasis agent [1].