Journal
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
Volume 40, Issue 7, Pages 3046-3059Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/07391102.2020.1844801
Keywords
p38α MAPK kinase inhibitor; EGFR T790M; C797S; molecular docking; MMGBSA; dynamic simulation
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Funding
- Indian Council of Medical Research (ICMR), New Delhi, Govt. of India [ISRM/12(11)/2019]
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Third-generation EGFR inhibitors like Osimertinib selectively target EGFR-T790M mutant and have good selectivity for wild-type EGFR. However, after treatment with Osimertinib, a C797S mutation may occur, rendering the tumor undruggable. Recently, trisubstituted imidazoles based on p38 alpha MAPK inhibitors have been developed as fourth-generation EGFR-TKIs to overcome C797S resistance.
The third-generation EGFR (epidermal growth factor receptor) inhibitors selectively and irreversibly target EGFR-T790M and other activating EGFR mutations. Osimertinib is the only FDA-approved third-generation inhibitor, which has a good potency against the EGFR-T790M mutant with minimal toxicities and excellent selectivity for wild-type EGFR. EGFR tertiary Cys797 to Ser797 (C797S) point mutation emanate rapidly after the treatment of osimertinib, which is an undruggable mutation to all three existing generation drugs. Recently, trisubstituted imidazoles were reported based on an off-target hit of a p38 alpha MAPK (mitogen-activated protein kinase) inhibitor as the fourth-generation EGFR-TKIs to overcome the C797S resistance by inhibiting the clinically relevant triple mutant kinase L858R/T790M/C797 EGFR. Here, we are reporting the clinical trial p38 alpha MAPK kinase inhibitors SD-06, Amgen 16, RWJ67657 and SCIO-323 as L858R/T790M/C797S EGFR TK inhibitors to overcome the problem of drug resistance in non-small cell lung cancer (NSCLC). Communicated by Ramaswamy H. Sarma
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