Mersal, Karim I. Abdel-Maksoud, Mohammed S. Ali, Eslam M. H. Ammar, Usama M. Zaraei, Seyed-Omar Haque, Md Mamunul Das, Tanuza Hassan, Noha F. Kim, Eunice EunKyeong Lee, Jun-Seok Park, Hajeung Lee, Kwan Hyi El-Gamal, Mohammed I. Kim, Hee-Kwon Ibrahim, Tamer M. Oh, Chang-Hyun 2024-01-19T08:03:36Z 2024-01-19T08:03:36Z 2023-11-08 2023-12 0223-5234 https://pubs.kist.re.kr/handle/201004/113058 A series of 36 pyrazol-4-yl pyridine derivatives (8a-i, 9a-i, 10a-i, and 11a-i) was designed, synthesized, and evaluated for its antiproliferative activity over NCI-60 cancer cell line panel and inhibitory effect against JNK isoforms (JNK1, JNK2, and JNK3). All the synthesized compounds were tested against the NCI-60 cancer cell line panel. Compounds 11b, 11c, 11g, and 11i were selected to determine their GI50s and exerted a superior potency over the reference standard SP600125 against the tested cell lines. 11c showed a GI50 of 1.28 mu M against K562 leukemic cells. Vero cells were used to assess 11c cytotoxicity compared to the tested cancer cells. The target compounds were tested against hJNK isoforms in which compound 11e exhibited the highest potency against JNK isoforms with IC50 values of 1.81, 12.7, and 10.5 nM against JNK1, JNK2, and JNK3, respectively. Kinase profiling of 11e showed higher JNK selectivity in 50 kinase panels. Compounds 11c and 11e showed cell population arrest at the G2/M phase, induced early apoptosis, and slightly inhibited beclin-1 production at higher concentrations in K562 leukemia cells relative to SP600125. NanoBRET assay of 11e showed intracellular JNK1 inhibition with an IC50 of 2.81 mu M. Also, it inhibited CYP2D6 and 3A4 with different extent and its hERG activity showed little cardiac toxicity with an IC50 of 4.82 mu M. hJNK3 was used as a template to generate the hJNK1 crystal structure to explore the binding mode of 11e (PDB ID: 8ENJ) with a resolution of 2.8 A and showed a typical type I kinase inhibition against hJNK1. Binding energy scores showed that selectivity of 11e towards JNK1 could be attributed to additional hydrophobic interactions relative to JNK3. English Elsevier BV Evaluation of novel pyrazol-4-yl pyridine derivatives possessing arylsulfonamide tethers as c-Jun N-terminal kinase (JNK) inhibitors in leukemia cells Article 10.1016/j.ejmech.2023.115779 1 European Journal of Medicinal Chemistry, v.261 European Journal of Medicinal Chemistry 261 N scie scopus 001086286400001 2-s2.0-85172260648 Chemistry, Medicinal Pharmacology & Pharmacy Article SIGNAL-TRANSDUCTION CANCER CELLS PROMOTES ACTIVATION EXPRESSION DISCOVERY AUTOPHAGY EFFICIENT SP600125 STRESS Arylsulfonamide Cancer JNK Leukemia Pyrazole