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DRUG:

BI-4020

i
Other names: BI-4020, BI4020, BI 4020
Company:
Boehringer Ingelheim
Drug class:
EGFR inhibitor
Related drugs:
4ms
Potential Utility of a 4th-Generation EGFR-TKI and Exploration of Resistance Mechanisms-An In Vitro Study. (PubMed, Biomedicines)
Ba/F3 cells with an osimertinib-resistant secondary mutation were refractory to all 3G TKIs tested (alflutinib, lazertinib, rezivertinib, almonertinib, and befotertinib)...HCC827BIR cells had MET gene amplification and were sensitive to a combination of capmatinib (MET-TKI) and BI4020...This study suggests that erlotinib may be more suitable than 4G TKIs to overcome secondary mutations after front-line osimertinib. We found that off-target mechanisms that cause resistance to earlier-generation TKIs will also cause resistance to 4G TKIs.
Preclinical • Journal
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MET (MET proto-oncogene, receptor tyrosine kinase)
|
Tagrisso (osimertinib) • erlotinib • Ameile (aumolertinib) • Tabrecta (capmatinib) • Ivesa (firmonertinib) • Lazcluze (lazertinib) • BI-4020 • Semena (befotertinib) • Rui Bi Da (rezivertinib)
8ms
Structural analysis of the macrocyclic inhibitor BI-4020 binding to EGFR kinase. (PubMed, ChemMedChem)
Structures show that BI-4020 is likely rendered selective due to interactions with the kinase domain hinge region as well as T790M, akin to Osimertinib. Additionally, BI-4020 is also rendered more potent due to its constrained macrocycle geometry as well as additional H-bonds to conserved K745 and T845 residues in both active and inactive conformations. These findings taken together show how this novel macrocyclic inhibitor is both highly potent and selective for mutant EGFR in a reversible mechanism and motivate structure- inspired approaches to developing targeted therapies in medicinal oncology.
Journal
|
EGFR (Epidermal growth factor receptor)
|
EGFR mutation • EGFR L858R • EGFR T790M • EGFR C797S
|
Tagrisso (osimertinib) • BI-4020
9ms
A macrocyclic kinase inhibitor overcomes triple resistant mutations in EGFR-positive lung cancer. (PubMed, NPJ Precis Oncol)
Brigatinib-based therapy was effective against osimertinib-resistant EGFR C797S mutants and is undergoing clinical studies. Molecular dynamics simulation revealed the binding mode and affinity between BI-4020 and EGFR mutants. This study identified potential therapeutic strategies using the new-generation macrocyclic EGFR inhibitor to overcome the emerging ultimate resistance mutants.
Journal
|
EGFR (Epidermal growth factor receptor)
|
EGFR mutation • EGFR T790M • EGFR C797S • EGFR S768I • EGFR positive • EGFR L747P
|
Tagrisso (osimertinib) • Alunbrig (brigatinib) • BI-4020
2years
Exploration of Secondary Resistant Mutations against Mobocertinib - in Vitro Study with Various EGFR Exon 20 Insertion Models (IASLC-ACLC 2022)
We also examined growth inhibitory effect of poziotinib, afatinib, CLN-081, erlotinib, osimertinib, brigatinib and BI4020 using the same Ba/F3 models. These findings indicate that T790M or C797S, depending on the activating mutations, will cause acquired resistance to mobocertinib in NSCLCs with EGFR exon 20 mutations. We also found a novel secondary mutation (F856V) that may confer acquired resistance to mobocertinib.
Preclinical • EGFR exon 20
|
EGFR (Epidermal growth factor receptor)
|
EGFR mutation • EGFR T790M • EGFR exon 20 insertion • EGFR C797S • EGFR exon 20 mutation
|
Tagrisso (osimertinib) • erlotinib • Gilotrif (afatinib) • Alunbrig (brigatinib) • Pozenveo (poziotinib) • Exkivity (mobocertinib) • BI-4020 • zipalertinib (CLN-081)