TY - JOUR
T1 - Design, synthesis, apoptotic, and antiproliferative effects of 5-chloro-3- (2-methoxyvinyl)-indole-2-carboxamides and pyrido[3,4-b]indol-1-ones as potent EGFRWT/EGFRT790M inhibitors
AU - Al-Wahaibi, Lamya H.
AU - Mohammed, Anber F.
AU - Abdel Rahman, Fatema El Zahraa S.
AU - Abdelrahman, Mostafa H.
AU - Gu, Xuyuan
AU - Trembleau, Laurent
AU - Youssif, Bahaa G.M.
N1 - Funding
This work was funded by Princess Nourah Bint Abdulrahman University Researchers Supporting Project Number [PNURSP2023R3], Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.
PY - 2023/5/31
Y1 - 2023/5/31
N2 - A new series of indole-2-carboxamides 5a-g, 6a-f and pyrido[3,4-b]indol-1-ones 7a and 7b have been developed as new antiproliferative agents that target both wild and mutant type EGFR. The antiproliferative effect of the new compounds was studied. 5c, 5d, 5f, 5 g, 6e, and 6f have the highest antiproliferative activity with GI50 values ranging from 29 nM to 47 nM in comparison to the reference erlotinib (GI50 = 33 nM). Compounds 5d, 5f, and 5 g inhibited EGFRWT with IC50 values ranging from 68 to 85 nM while the GI50 of erlotinib is 80 nM. Moreover, compounds 5f and 5 g had the most potent inhibitory activity against EGFRT790M with IC50 values of 9.5 ± 2 and 11.9 ± 3 nM, respectively, being equivalent to the reference osimertinib (IC50 = 8 ± 2 nM). Compounds 5f and 5 g demonstrated excellent caspase-3 protein overexpression levels of 560.2 ± 5.0 and 542.5 ± 5.0 pg/mL, respectively, being more active than the reference staurosporine (503.2 ± 4.0 pg/mL). they also increase the level of caspase 8, and Bax while decreasing the levels of anti-apoptotic Bcl2 protein. Computational docking studies supported the enzyme inhibition results and provided favourable dual binding modes for both compounds 5f and 5 g within EGFRWT and EGFRT790M active sites. Finally, in silico ADME/pharmacokinetic studies predict good safety and pharmacokinetic profile of the most active compounds.
AB - A new series of indole-2-carboxamides 5a-g, 6a-f and pyrido[3,4-b]indol-1-ones 7a and 7b have been developed as new antiproliferative agents that target both wild and mutant type EGFR. The antiproliferative effect of the new compounds was studied. 5c, 5d, 5f, 5 g, 6e, and 6f have the highest antiproliferative activity with GI50 values ranging from 29 nM to 47 nM in comparison to the reference erlotinib (GI50 = 33 nM). Compounds 5d, 5f, and 5 g inhibited EGFRWT with IC50 values ranging from 68 to 85 nM while the GI50 of erlotinib is 80 nM. Moreover, compounds 5f and 5 g had the most potent inhibitory activity against EGFRT790M with IC50 values of 9.5 ± 2 and 11.9 ± 3 nM, respectively, being equivalent to the reference osimertinib (IC50 = 8 ± 2 nM). Compounds 5f and 5 g demonstrated excellent caspase-3 protein overexpression levels of 560.2 ± 5.0 and 542.5 ± 5.0 pg/mL, respectively, being more active than the reference staurosporine (503.2 ± 4.0 pg/mL). they also increase the level of caspase 8, and Bax while decreasing the levels of anti-apoptotic Bcl2 protein. Computational docking studies supported the enzyme inhibition results and provided favourable dual binding modes for both compounds 5f and 5 g within EGFRWT and EGFRT790M active sites. Finally, in silico ADME/pharmacokinetic studies predict good safety and pharmacokinetic profile of the most active compounds.
KW - ADME
KW - antiproliferative
KW - apoptosis
KW - EGFR
KW - Indole
KW - mutation
KW - resistance
UR - http://www.scopus.com/inward/record.url?scp=85160634957&partnerID=8YFLogxK
U2 - 10.1080/14756366.2023.2218602
DO - 10.1080/14756366.2023.2218602
M3 - Article
C2 - 37254958
AN - SCOPUS:85160634957
SN - 1475-6374
VL - 38
JO - Journal of enzyme inhibition and medicinal chemistry
JF - Journal of enzyme inhibition and medicinal chemistry
IS - 1
M1 - 2218602
ER -