Related Experiment Video
Updated: Jun 5, 2025
A Strategy to Identify Compounds that Affect Cell Growth and Survival in Cultured Mammalian Cells at Low-to-Moderate Throughput
Published on: September 22, 2019
Discovery of a Novel Mutant-Selective Epidermal Growth Factor Receptor Inhibitor Using an In Silico Enabled Drug
Hideyuki Igawa1, Zef A Konst1, Eric Therrien1
1Schrödinger Inc., New York, New York 10036, United States.
Abstract:
Despite the success of first, second, and third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for non-small cell lung cancer with classical EGFR mutations (L858R or Exon 19 deletions), disease progression occurs due to the acquisition of T790M and C797S resistance. Herein, we report a physics-based computationally driven lead identification approach that identified structurally unique imidazo[3.2-b]pyrazoles as reversible and wild-type-sparing EGFR TKIs of classical mutations bearing both T790M and C797S. During profiling of imidazo[3.2-b]pyrazoles, we elucidated the bioactivation mechanism causing CYP3A4/5 time-dependent inhibition (TDI) and found key modifications to mitigate the TDI. Compound 31 inhibited EGFR L858R/T790M/C797S in biochemical assays with a Ki = 2.1 nM and EGFR del19/T790M/C797S in a Ba/F3 cellular assay with an IC50 = 56.9 nM. The deuterated analogue of 31 (38) demonstrated dose-dependent tumor growth inhibition in a Ba/F3 EGFR del19/T790M/C797S CDX model by 47% at 50 mg/kg BID and 92% at 100 mg/kg BID.
Insights
New imidazo[3.2-b]pyrazoles target resistant EGFR mutations in lung cancer. These compounds overcome T790M and C797S resistance, offering a potential new treatment for non-small cell lung cancer.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Oncology
Background:
- First, second, and third-generation EGFR TKIs are effective for NSCLC with classical mutations.
- Acquired resistance via T790M and C797S mutations limits TKI efficacy.
- Novel therapeutic strategies are needed to overcome resistance in EGFR-mutated NSCLC.
Purpose of the Study:
- To identify novel, wild-type-sparing EGFR TKIs targeting classical mutations with T790M and C797S resistance.
- To elucidate the bioactivation mechanism and mitigate time-dependent inhibition (TDI) by CYP3A4/5.
- To evaluate the efficacy of identified compounds in preclinical models.
Main Methods:
- Physics-based computational approaches for lead identification.
- Synthesis and profiling of imidazo[3.2-b]pyrazoles.
- Biochemical and cellular assays to assess EGFR inhibition.
- Pharmacokinetic and efficacy studies in preclinical models.
Main Results:
- Structurally unique imidazo[3.2-b]pyrazoles were identified as potent EGFR inhibitors.
- Compound 31 demonstrated high affinity (K_i = 2.1 nM) for EGFR L858R/T790M/C797S.
- Compound 31 (IC50 = 56.9 nM) and its deuterated analog 38 showed significant tumor growth inhibition in a preclinical model.
Conclusions:
- Imidazo[3.2-b]pyrazoles represent a promising class of reversible, wild-type-sparing EGFR inhibitors.
- Key modifications successfully mitigated CYP3A4/5 time-dependent inhibition.
- Compound 38 demonstrated significant in vivo efficacy, warranting further development for NSCLC treatment.
More Related Videos
07:32Screening and Identification of Small Peptides Targeting Fibroblast Growth Factor Receptor2 using a Phage Display Peptide Library
Published on: September 30, 2019
13:34A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds
Published on: April 6, 2016
