FORX-428 is an orally active, selective poly (ADP-ribose) glycohydrolase ( PARG ) inhibitor. FORX-428 reversibly inhibits PARG, thereby blocking PAR chain dissociation, inhibiting DNA repair, inducing tumor cell death, and targeting replication stress in cancer cells. FORX-428 can be used in the research of ovarian cancer and triple-negative breast cancer [1].
In Vivo, FORX-428 (once daily; oral administration; for approximately 20 days) induces robust and durable tumor regression in ovarian cancer patient-derived xenograft (PDX) models[1]. FORX-428 (once daily; oral administration; for approximately 20 days) exerts a significant tumor growth inhibitory effect in a triple-negative breast cancer model (MDA-MB-436; HRD+; acquired resistance to PARP inhibitors)[1]. FORX-428 (10 mg/kg or 100 mg/kg; once daily; p.o.; 120 days) induces long-lasting tumor regression and sustains tumor control after discontinuation in a PARP inhibitor-resistant ovarian cancer PDX model harboring BRCA1 revertant mutations[1].
In Vitro, FORX-428 potently inhibits purified PARG, with a Kd value of 0.3 nM, an IC50 value of 0.06 nM, and a target residence time as long as 104 minutes[1]. FORX-428 inhibits the proliferation of MDA-MB-436 (IC50 = 19 nM), HCC1937 (IC50 = 17 nM), HCC1428 (IC50 = 1.7 nM), RMUG-S (IC50 < 0.5 nM), and Kuramochi (IC50 = 0.6 nM) cells, but exerts no potent inhibitory effect on the viability of U2OS cells, with an IC50 greater than 5000 nM[1].
References:
[1]. Zenke, et al. "FORX-428: A best-in class PARG inhibitor with promising anti-tumor activity in preclinical cancer models." Molecular Cancer Therapeutics. Vol. 24. No. 10. 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA: AMER ASSOC CANCER RESEARCH, 2025.
[2]. Zenke, et al. "FORX-428: Exploiting PARG inhibition to target replication stress in cancer cells." Cancer Research 86.7_Supplement (2026): 1748-1748.
In Vivo, FORX-428 (once daily; oral administration; for approximately 20 days) induces robust and durable tumor regression in ovarian cancer patient-derived xenograft (PDX) models[1]. FORX-428 (once daily; oral administration; for approximately 20 days) exerts a significant tumor growth inhibitory effect in a triple-negative breast cancer model (MDA-MB-436; HRD+; acquired resistance to PARP inhibitors)[1]. FORX-428 (10 mg/kg or 100 mg/kg; once daily; p.o.; 120 days) induces long-lasting tumor regression and sustains tumor control after discontinuation in a PARP inhibitor-resistant ovarian cancer PDX model harboring BRCA1 revertant mutations[1].
In Vitro, FORX-428 potently inhibits purified PARG, with a Kd value of 0.3 nM, an IC50 value of 0.06 nM, and a target residence time as long as 104 minutes[1]. FORX-428 inhibits the proliferation of MDA-MB-436 (IC50 = 19 nM), HCC1937 (IC50 = 17 nM), HCC1428 (IC50 = 1.7 nM), RMUG-S (IC50 < 0.5 nM), and Kuramochi (IC50 = 0.6 nM) cells, but exerts no potent inhibitory effect on the viability of U2OS cells, with an IC50 greater than 5000 nM[1].
References:
[1]. Zenke, et al. "FORX-428: A best-in class PARG inhibitor with promising anti-tumor activity in preclinical cancer models." Molecular Cancer Therapeutics. Vol. 24. No. 10. 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA: AMER ASSOC CANCER RESEARCH, 2025.
[2]. Zenke, et al. "FORX-428: Exploiting PARG inhibition to target replication stress in cancer cells." Cancer Research 86.7_Supplement (2026): 1748-1748.