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Chronicles of EGFR Tyrosine Kinase Inhibitors: Targeting EGFR C797S Containing Triple Mutations
( Krishna Babu Duggirala ),( Yujin Lee ),( Kwangho Lee ) 한국응용약물학회 2022 Biomolecules & Therapeutics(구 응용약물학회지) Vol.30 No.1
Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase widely expressed in many cancers such as non-small cell lung cancer (NSCLC), pancreatic cancer, breast cancer, and head and neck cancer. Mutations such as L858R in exon 21, exon 19 truncation (Del19), exon 20 insertions, and others are responsible for aberrant activation of EGFR in NSCLC. First-generation EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib have clinical benefits for EGFR-sensitive (L858R and Del19) NSCLC patients. However, after 10-12 months of treatment with these inhibitors, a secondary T790M mutation at the gatekeeper position in the kinase domain of EGFR was identified, which limited the clinical benefits. Second-generation EGFR irreversible inhibitors (afatinib and dacomitinib) were developed to overcome this T790M mutation. However, their lack of selectivity toward wild-type EGFR compromised their clinical benefits due to serious adverse events. Recently developed third-generation irreversible EGFR TKIs (osimertinib and lazertinib) are selective toward driving mutations and the T790M mutation, while sparing wildtype EGFR activity. The latest studies have concluded that their efficacy was also compromised by additional acquired mutations, including C797S, the key residue cysteine that forms covalent bonds with irreversible inhibitors. Because second- and thirdgeneration EGFR TKIs are irreversible inhibitors, they are not effective against C797S containing EGFR triple mutations (Del19/ T790M/C797S and L858R/T790M/C797S). Therefore, there is an urgent unmet medical need to develop next-generation EGFR TKIs that selectively inhibit EGFR triple mutations via a non-irreversible mechanism.
Lee Yujin,Jang Jiyoon,Bibi Maimoona,Duggirala Krishna Babu,Ji Sang Hee,Lee Ji Hun,Ahn Sunjoo,Song Jin Sook,Chae Chong Hak,Kim Seong Hwan,Lee Kwangho 대한화학회 2021 Bulletin of the Korean Chemical Society Vol.42 No.6
Apoptosis signal-regulating kinase 1 (ASK1) is a member of mitogen-activated protein kinase kinase kinase (MAP3K) family that involves downstream phosphorylation of MAP kinases, c-Jun N-terminal kinases, and p38 MAP kinases. ASK1 inhibitors could possibly be beneficial for ameliorating the development and progression of diseases. Especially, ASK1 has been of interest as one of therapeutic targets for nonalcoholic fatty liver disease as the most common chronic liver diseases including simple steatosis and nonalcoholic steatohepatitis. In this manuscript, novel ASK1 inhibitor lead KTA-29 which has an imidazo [1,2-b]pyridazine core with novel C6-bicycloheptaneimidazole is disclosed. With the novel imidazo[1,2-b] pyridazine core, structure-activity-relationship study for ASK1 potency is described and KTA-29 affinity toward ASK1 with molecular modeling study is explained.