HF-125 is an orally active, highly selective small-molecule inhibitor of Tribbles 2 (TRIB2). HF-125 promotes the destabilization and degradation of TRIB2 protein via the proteasome pathway. HF-125 downregulates neuroendocrine markers, induces cell cycle arrest and apoptosis, inhibits tumor cell colony formation and invasion, and reverses tumor cell resistance to Enzalutamide. HF-125 significantly inhibits tumor growth in SCID mouse xenograft models, and exerts synergistic inhibitory effects when combined with Enzalutamide. HF-125 can be used in research related to prostate cancer [1].
In Vivo, HF-125 (40 mg/kg; p.o.; daily; 28 days) strongly inhibits enzalutamide-resistant neuroendocrine prostate cancer tumor growth in SCID SHO mice, with significant downregulation of TRIB2 and associated neuroendocrine and proliferation markers, and no overt toxicity[1].
In Vitro, HF-125 (2-4 μM) induces proteasome-dependent degradation of TRIB2 protein in LN-TRIB2 cells[1]. HF-125 (1-2 μM; 72 h) re-sensitizes LNCaP-ENR, MDA PCa-2b-ENR, LN-TRIB2, and MDA PCa-2b-TRIB2 prostate cancer cells to Enzalutamide [1]. HF-125 (1 μM; 24 h) enhances Enzalutamide-induced DNA fragmentation and cell death in LNCaP-ENR and MDA PCa-2b-ENR prostate cancer cells[1]. HF-125 (2-8 μM; 72 h) reduces cell viability in LN-Trio2, LN-Trib2, NCI-H660, NCI-H660-01, LASCPC-01, and TRAMP-C1 NEPC cell lines in a dose-dependent manner[1]. HF-125 (2-6 μM; 48 h) downregulates TRIB2 and neuroendocrine marker proteins (N-Myc, EZH2, ASCL1, CGA, ENO2, SYP) while upregulating AR and PSA in LN-TRIB2 cells[1]. HF-125 (2-6 μM; 24 h) induces dose-dependent apoptosis in LN-TRIB2 cells[1]. HF-125 (2-4 μM; 24 h) induces G2M phase cell cycle arrest in LN-TRIB2 cells[1]. HF-125 (2-6 μM; 14 days) reduces the clonogenic potential of LN-TRIB2 cells in a dose-dependent manner[1]. HF-125 (2-6 μM; 16 h) reduces the invasive capacity of LN-TRIB2 cells in a dose-dependent manner[1]. HF-125 (1 μM; 72 h) synergizes with 10 μM enzalutamide to reduce cell viability in LNCaP and MDA PCa-2b prostate cancer cells[1]. HF-125 (1 μM; 16 h) synergizes with 10 μM enzalutamide to inhibit invasion in LNCaP and MDA PCa-2b prostate cancer cells after 16 hours of co-treatment[1].
References:
[1]. Chowdhury SG, et al. HF-I25, a first-in-class computer-modeled novel inhibitor of Tribbles 2, for therapy of enzalutamide resistant, neuroendocrine prostate cancer. bioRxiv. 2026;2026.04.27.720588.
In Vivo, HF-125 (40 mg/kg; p.o.; daily; 28 days) strongly inhibits enzalutamide-resistant neuroendocrine prostate cancer tumor growth in SCID SHO mice, with significant downregulation of TRIB2 and associated neuroendocrine and proliferation markers, and no overt toxicity[1].
In Vitro, HF-125 (2-4 μM) induces proteasome-dependent degradation of TRIB2 protein in LN-TRIB2 cells[1]. HF-125 (1-2 μM; 72 h) re-sensitizes LNCaP-ENR, MDA PCa-2b-ENR, LN-TRIB2, and MDA PCa-2b-TRIB2 prostate cancer cells to Enzalutamide [1]. HF-125 (1 μM; 24 h) enhances Enzalutamide-induced DNA fragmentation and cell death in LNCaP-ENR and MDA PCa-2b-ENR prostate cancer cells[1]. HF-125 (2-8 μM; 72 h) reduces cell viability in LN-Trio2, LN-Trib2, NCI-H660, NCI-H660-01, LASCPC-01, and TRAMP-C1 NEPC cell lines in a dose-dependent manner[1]. HF-125 (2-6 μM; 48 h) downregulates TRIB2 and neuroendocrine marker proteins (N-Myc, EZH2, ASCL1, CGA, ENO2, SYP) while upregulating AR and PSA in LN-TRIB2 cells[1]. HF-125 (2-6 μM; 24 h) induces dose-dependent apoptosis in LN-TRIB2 cells[1]. HF-125 (2-4 μM; 24 h) induces G2M phase cell cycle arrest in LN-TRIB2 cells[1]. HF-125 (2-6 μM; 14 days) reduces the clonogenic potential of LN-TRIB2 cells in a dose-dependent manner[1]. HF-125 (2-6 μM; 16 h) reduces the invasive capacity of LN-TRIB2 cells in a dose-dependent manner[1]. HF-125 (1 μM; 72 h) synergizes with 10 μM enzalutamide to reduce cell viability in LNCaP and MDA PCa-2b prostate cancer cells[1]. HF-125 (1 μM; 16 h) synergizes with 10 μM enzalutamide to inhibit invasion in LNCaP and MDA PCa-2b prostate cancer cells after 16 hours of co-treatment[1].
References:
[1]. Chowdhury SG, et al. HF-I25, a first-in-class computer-modeled novel inhibitor of Tribbles 2, for therapy of enzalutamide resistant, neuroendocrine prostate cancer. bioRxiv. 2026;2026.04.27.720588.