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Ref Type Abstract
PMID
Authors Susan S. Liu-Chen; Jufang Lin; Jingyu Hu; Yanchao Liu; Weibo Zhang; Zhixiong Zhang; Yan Ding; Jinqiu Liu; Kevin Chen; Shaojing Hu
Title Abstract 1965: 3HP-2827-high selective inhibitor of FGFR2, a best-in-class therapy for FGFR2-driven solid tumors
Journal Vol Issue Date Pages Journal Short Title
Cancer Research 84 6_supplement March 22 2024 1965 Cancer Res
URL https://aacrjournals.org/cancerres/article/84/6_Supplement/1965/738272
Abstract Text FDA-approved pan-FGFR inhibitors bring encouraging results in solid tumors. However, resistance mechanisms and side effect profiles may limit their clinical utility. We designed 3HP-2827, a highly selective and potent small molecule inhibitor of FGFR2, to treat solid tumors harboring FGFR2 alterations, including amplifications, mutations, and fusions to overcome these limitations. 3HP-2827 inhibits FGFR2 enzyme activity with more than 1623-fold selectivity over FGFR1 and FGFR3. 3HP-2827 inhibits cell proliferation with IC50 <10 nM and 30 nM in FGFR2 amplified and FGFR2-mutant cancer cell lines, respectively. 3HP-2827 demonstrates high kinome selectivity for FGFR2 against a panel of 485 human kinases, resulting in 90.1% inhibition of FGFR2, and no other kinases showed greater than 75% inhibition. 3HP-2827 leads only modest activity at 10 µM against PDE4D2 and LCK in 44 distinct common adverse drug reaction targets, supporting its high degree of safety. 3HP-2827 also demonstrates a dose-dependent inhibition of phosphorylation of FGFR2 and FGFR2 signaling pathway nodes, including ERK and AKT, in the FGFR2-dependent cancer cell line. In vivo, 3HP-2827 demonstrates potent antitumor activity in cell- and patient-derived xenograft mouse models, including FGFR2-amplified gastric cancer, FGFR2-mutant (N549K) endometrial cancer, FGFR2 fusion ICC and gastric cancers. Strikingly, 3HP-2827 demonstrates superior activity in patient-derived ICC and gastric cancer, cell-derived endometrial cancer (CDX) in tumor and pFGFR2 inhibitions. In the ICC PDX model, 3HP-2827 also induces the regression of pemigatinib-resistant tumors. 3HP-2827 is well tolerated in the toxicology studies, and no hyperphosphatemia or tissue mineralization is observed at 150 mg/kg/kg/day in rats and 120 mg/kg/day in dogs. The data support that 3HP-2827, a potential to be a best-in-class selective FGFR2 inhibitor, will be studying clinically at the beginning of 2024.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
3HP-2827 3HP-2827 4 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
3HP-2827 3HP 2827|3HP2827 FGFR2 Inhibitor 23 3HP-2827 selectively inhibits FGFR2, potentially resulting in decreased cell proliferation and tumor growth (Cancer Res (2024) 84 (6_Supplement): 1965).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR2 fusion intrahepatic cholangiocarcinoma predicted - sensitive 3HP-2827 Preclinical - Pdx Actionable In a preclinical study, 3HP-2827 treatment demonstrated antitumor activity and induced tumor regression in a patient-derived xenograft (PDX) model of intrahepatic cholangiocarcinoma harboring an FGFR2 fusion (Cancer Res (2024) 84 (6_Supplement): 1965). detail...
FGFR2 N549K endometrial cancer predicted - sensitive 3HP-2827 Preclinical - Cell line xenograft Actionable In a preclinical study, 3HP-2827 treatment demonstrated antitumor activity in a cell line xenograft model of endometrial cancer harboring FGFR2 N549K (Cancer Res (2024) 84 (6_Supplement): 1965). detail...
FGFR2 fusion stomach cancer predicted - sensitive 3HP-2827 Preclinical - Pdx Actionable In a preclinical study, 3HP-2827 treatment demonstrated antitumor activity in a patient-derived xenograft (PDX) model of gastric cancer harboring an FGFR2 fusion (Cancer Res (2024) 84 (6_Supplement): 1965). detail...
FGFR2 amp stomach cancer predicted - sensitive 3HP-2827 Preclinical - Pdx Actionable In a preclinical study, 3HP-2827 treatment demonstrated antitumor activity in a patient-derived xenograft (PDX) model of gastric cancer with FGFR2 amplification (Cancer Res (2024) 84 (6_Supplement): 1965). detail...