Abstract 7271: Proteasome inhibitor FHND6091: A potent therapeutic candidate forPTEN-deficient cholangiocarcinoma
Authors: Zhu Yongqiang , Shi Jingmiao , Li Chenhui 
Published: March 2024

Background: Cholangiocarcinoma (CCA), characterized by high genetic heterogeneity, poses a significant challenge due to limited therapeutic options. Notably, the tumor suppressor gene PTEN is frequently altered in more than 50% of CCA clinical specimens. PTEN deficiency enhances proteasome subunit expression and proteasome proteolytic activity, and facilitates the potential therapeutic efficacy of proteasome inhibitors in CCA. The proteasome inhibitor FHND6091, a novel drug developed by Jiangsu Chia Tai Fenghai Pharmaceutical Co., Ltd., has obtained IND approval from NMPA and is currently undergoing a first-in-human phase 1 trial for multiple myeloma (MM) and mantle cell lymphoma (MCL).

Method: This study employed a comprehensive approach, encompassing both in vitro and in vivo pharmacology studies. The investigation involved purified human proteasome activity assays, cell viability assays, and in vivo anti-tumor activity studies utilizing a cholangiocarcinoma patient-derived xenograft (CCA PDX) model with PTEN deficiency.

Results: FHND6091 exhibited potent inhibitory effects on the β5 subunit of the 20S proteasome, with IC50 value of 2.22 nM. In cell viability assessments, FHND6091 demonstrated selective efficacy in PTEN-deficient CCA cell lines, with IC50 value of 5.87 nM in HCCC-9810 (PTEN deletion, homozygous loss of exon 6 to 9) and 10.08 nM in RBE (PTEN intact expression). In a PDX xenograft model with PTEN deficiency, gavage administration of FHND6091 BIW at 1.0 mg/kg (first week)/1.5 mg/kg (subsequent two weeks) exhibited advanced anti-tumor activity (TGI = 52.32%) compared to intraperitoneal administration of Bortezomib at 0.5 mg/kg BIW (TGI = 31.88%). Tissue distribution studies in rats revealed the preference of FHND6091 for liver accumulation, with an exposure (AUC0-t) approximately 44 times that of plasma after a single dose. These data corroborated that FHND6091 could achieve a specific level of exposure in the target organ liver.

Conclusion: FHND6091, characterized by its irreversibility, high potency and oral bioavailability, emerges as a promising proteasome inhibitor for the treatment of both hematologic and solid tumors. These findings strongly support FHND6091 as a potential candidate for the treatment of CCA in clinical settings. Furthermore, the regulating of sensitivity to proteasome inhibitors by the PTEN status extends beyond cholangiocarcinoma to encompass various human cancers, such as ovarian, prostate, and digestive system malignancies. This broader implication establishes a theoretical foundation supporting the potential efficacy of FHND6091 as a therapeutic agent for solid tumors.

Citation Format: Yongqiang Zhu, Jingmiao Shi, Chenhui Li. Proteasome inhibitor FHND6091: A potent therapeutic candidate forPTEN-deficient cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7271.