Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl Click chemistry for improvement in selectivity of quinazoline-based kinase inhibitors for mutant epidermal growth factor receptors Jiho Song, Soyeon Jang, Jung Wuk Lee, Danbee Jung, Seul Lee, Kyung Hoon Min ⁎ College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea ARTICLEINFO Keywords: Epidermal growth factor receptor Click chemistry Quinazoline Mutant selective kinase inhibitor ABSTRACT Discovery of mutant-selective kinase inhibitors is one of the challenges in medicinal chemistry and is a main issueforepidermalgrowthfactorreceptor(EGFR)tyrosinekinaseinhibitors.Wetriedtoimprovetheselectivity of pan-HER inhibitors for mutant EGFRs. Utilizing click chemistry, triazole-tethered quinazoline derivatives weresynthesized,basedonaquinazolinescafoldshowingpan-HERinhibition.Therepresentativecompound 5j exhibited 17- and 52-fold improved selectivity for EGFR L858R/T790M over wild-type EGFR and HER2, re- spectively, and demonstrated 6.7-fold more potent antiproliferative activity against PC9 cells harboring EGFR- activating mutation than geftinib. Although the described quinazolines did not surpass pyrimidines as 3rd generation EGFR inhibitors in terms of selectivity for mutant EGFRs, our approach might provide information that would help in the identifcation of mutant-selective compounds among pan-HER inhibitors using the qui- nazoline scafold. Non-small cell lung cancer (NSCLC) accounts for over 80% of all lung cancers. 1 The incidence rate of epidermal growth factor receptor (EGFR)-dependent NSCLC is 10% globally and approximately 30–40% in East Asian patients; EGFR-dependent NSCLC has activating muta- tions in EGFR including L858R or exon 19 deletion in the kinase do- main. 2–4 EGFRtyrosinekinaseinhibitors(TKIs)exhibitahighresponse rate in patients with activating mutations of EGFR. 2 EGFR TKIs are classifed into two types: reversible inhibitors including geftinib and erlotinib (1st gen EGFR TKIs) and irreversible inhibitors including afatinib and osimertinib (2nd and 3rd gen EGFR TKIs). 5 The 2nd gen EGFR TKIs exhibit strong inhibition for all the ErbB family members including EGFR (ErbB1), ErbB2 (HER2), and ErbB4 (HER4). They are pan-HER inhibitors, while 1st gen EGFR TKIs mainly inhibit both wild- type and activating mutant EGFR. The mutation of a gatekeeper residue, T790M, results in resistance against 1st and 2nd gen EGFR TKIs, which are found in approximately 50% of patients who are resistant to 1st gen EGFR TKIs. 1,6 The irre- versible pan-HER inhibitors including afatinib, which were approved for EGFR-dependent NSCLC as a 1st line therapy, could overcome the acquiredresistancebyT790Mbecausetheycouldcompletelyeliminate the activity of T790M mutated-kinase by forming a covalent bond. 7 Although pan-HER inhibitors exhibited high potential to treat NSCLC harboring EGFR T790M in preclinical trials, irreversible inhibitors did not exhibit a therapeutic efect in patients with T790M because of strong inhibition of wild-type EGFR before reaching a sufcient ther- apeutic dose to inhibit EGFR T790M. 8 Inhibition of either wild-type EGFR or HER2 can lead to severe skin rashes and diarrhea as well- known on-target adverse efects. 9 In addition, inhibition of HER2 (e.g., trastuzumab, anti-HER2 antibody) can result in cardiovascular adverse efects including left ventricular (LV) dysfunction. 10 Afatinib exhibits adverse efects of grade 3 in a large number patients although its ef- cacywasconsiderable. 11 Reductionoftheadverseefectsresulting from inhibitionofwild-typeEGFRandHER2shouldmakethe2ndgenEGFR TKIs more useful (Fig. 1). The 3rd gen EGFR TKIs including WZ4002 and osimertinib showed highselectivityforEGFRT790Moverwild-typeEGFR. 12,13 The3rdgen EGFR TKIs are structurally characterized by a pyrimidine scafold, while 1st and 2nd gen EGFR TKIs have a quinazoline scafold. 5 Our trials to fnd mutant-selective EGFR TKIs commenced with a quinazo- line scafold of non-selective 2nd gen EGFR TKI because quinazolines including erlotinib, geftinib, and afatinib showed high selectivity for theErbBfamilyaskinaseinhibitors. 14 Herein,wedescribeastrategyto improve the selectivity of quinazoline derivatives for mutant EGFR throughclickchemistry,whichisapowerfulsyntheticapproachindrug discovery. 15 First, we focused on derivatization at the 7-position of the quina- zolinescafold.Aknowncompound 4 wasconsideredasanappropriate substrate for our strategy. As shown in Table 1, compound 4 showed https://doi.org/10.1016/j.bmcl.2018.12.020 Received 25 October 2018; Received in revised form 30 November 2018; Accepted 10 December 2018 ⁎ Corresponding author. E-mail address: khmin@cau.ac.kr (K.H. Min). Bioorganic & Medicinal Chemistry Letters xxx (xxxx) xxx–xxx 0960-894X/ © 2018 Elsevier Ltd. All rights reserved. Please cite this article as: Song, J., Bioorganic & Medicinal Chemistry Letters, https://doi.org/10.1016/j.bmcl.2018.12.020