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BPI-28592 as a novel second generation inhibitor for NTRK fusion tumors

Jin Sheng, Hong Chen, Bang Fu, Hongming Pan, Jia‐Bing Wang, Weidong Han · 2024 · 6 citationsRead the paper

Aberrant activation of tropomyosin receptor kinases (TRKs) is a well-defined oncogenic driver for neurotrophic tropomyosin receptor kinase (NTRK)-fusion cancers, and acquired resistant mutations have emerged with clinical use of the first-generation TRK inhibitors. Here we present BPI-28592, a novel second-generation TRK inhibitor with efficacy against TRK fusion-positive cancers, including those with resistant mutations. Docking simulations indicated no steric hindrance between BPI-28592 and TRK mutants, suggesting its potential to overcome drug resistance. Biochemical assays showed strong inhibition and high selectivity against TRKA, TRKB, and TRKC. The inhibitor significantly reduced cell proliferation and blocked TRK signaling. In vivo studies demonstrated effective tumor suppression in xenograft models harboring TRK fusions with or without resistant mutations. Clinically, BPI-28592 achieved a complete response in a patient with malignant melanoma carrying an AP3S2-NTRK3 fusion (Clinicaltrials. gov identifier: NCT05302843).

What the full text shows

Working prototype
  • BPI-28592 achieved a complete response in a patient with AP3S2-NTRK3 fusion malignant melanoma. — Complete response, maintained for >2 years (100 mg BID oral dosing)
  • BPI-28592 demonstrated high binding affinity and selectivity for TRK family kinases. — Kd values: TRKA 0.23 nM, TRKB 0.55 nM, TRKC 1.1 nM (KinomeScan and KdELECT platforms)
  • BPI-28592 inhibited TRKA phosphorylation at very low concentrations. — Potent inhibition at 0.1 nM (Ba/F3-TPM3-NTRK1 cells)
  • BPI-28592 showed superior or comparable tumor suppression to larotrectinib in multiple xenograft models. — Doses 1.5 mg/kg to 15 mg/kg (CDX (Ba/F3-TPM3-NTRK1, Ba/F3-ETV6-NTRK3, KM12) and PDX (TPM3-NTRK1) models)
  • BPI-28592 effectively suppressed tumors harboring first-generation inhibitor resistance mutations. — Stronger suppression than larotrectinib at 75 mg/kg (Ba/F3 xenograft with LMNA-NTRK1 G595R mutation)
  • BPI-28592 exhibited high potency against multiple TRK mutants. — IC50 values in the two-digit nanomolar range (Ba/F3 cell lines with resistance mutations)
Setup
Kinome profiling of 468 kinases; cell lines including KM12 and engineered Ba/F3; 5 xenograft models (4 CDX, 1 PDX); one human patient case study.
How
Structural modeling-guided rational design was used to create a nonmacrocyclic inhibitor. Efficacy was validated via biochemical kinase assays, cell proliferation assays, xenograft models (CDX and PDX), and a Phase I clinical dose-increasing study.
Limitations
Clinical efficacy demonstrated in a single patient case report. · Dose differences in animal models may not directly translate to human dosing due to species-specific PK profiles.

Summarized by Gemma 4 from the open-access full text · 8 Oct 2026. Read it