TY - JOUR
T1 - Novel Allosteric Inhibitor-Derived AKT Proteolysis Targeting Chimeras (PROTACs) Enable Potent and Selective AKT Degradation in KRAS/BRAF Mutant Cells
AU - Yu, Xufen
AU - Xu, Jia
AU - Cahuzac, Kaitlyn M.
AU - Xie, Ling
AU - Shen, Yudao
AU - Chen, Xian
AU - Liu, Jing
AU - Parsons, Ramon E.
AU - Jin, Jian
N1 - Funding Information:
J.J. acknowledges support from an endowed professorship by the Icahn School of Medicine at Mount Sinai. This research was supported by Grant R35CA220491 (to R.E.P.) from the National Cancer Institute (NCI) at the National Institutes of Health (NIH). R.E.P. and J.J. are also supported by Grant P30 CA196521 from the NCI at the NIH. J.X. is supported by T32 Postdoc Fellow Training Grant T32CA078207 and Leo and Julia Forchheimer Foundation Postdoc Fellowship. This work utilized the NMR spectrometer systems at Mount Sinai acquired with funding from National Institutes of Health SIG Grants 1S10OD025132 and 1S10OD028504.
Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.
PY - 2022/10/27
Y1 - 2022/10/27
N2 - AKT is an important target for cancer therapeutics. Significant advancements have been made in developing ATP-competitive and allosteric AKT inhibitors. Recently, several AKT proteolysis targeting chimeras (PROTACs) derived from ATP-competitive AKT inhibitors have been reported, including MS21. While MS21 potently degraded AKT and inhibited the growth in tumor cells harboring PI3K/PTEN pathway mutation, it was largely ineffective in degrading AKT in KRAS/BRAF mutated cells as a single agent. To overcome the AKT degradation resistance in KRAS/BRAF mutated cells, we developed novel AKT PROTACs derived from an AKT allosteric inhibitor, including degrader 62 (MS15). 62 displayed potent and selective AKT degradation activity and potent antiproliferative activity in KRAS/BRAF mutated cancer cells, in addition to PI3K/PTEN mutated cancer cells. Furthermore, 62 was bioavailable in mice through intraperitoneal administration. Overall, 62 is a valuable chemical tool to degrade AKT in cells harboring KRAS/BRAF mutation and expands the tool box for pharmacologically modulating AKT.
AB - AKT is an important target for cancer therapeutics. Significant advancements have been made in developing ATP-competitive and allosteric AKT inhibitors. Recently, several AKT proteolysis targeting chimeras (PROTACs) derived from ATP-competitive AKT inhibitors have been reported, including MS21. While MS21 potently degraded AKT and inhibited the growth in tumor cells harboring PI3K/PTEN pathway mutation, it was largely ineffective in degrading AKT in KRAS/BRAF mutated cells as a single agent. To overcome the AKT degradation resistance in KRAS/BRAF mutated cells, we developed novel AKT PROTACs derived from an AKT allosteric inhibitor, including degrader 62 (MS15). 62 displayed potent and selective AKT degradation activity and potent antiproliferative activity in KRAS/BRAF mutated cancer cells, in addition to PI3K/PTEN mutated cancer cells. Furthermore, 62 was bioavailable in mice through intraperitoneal administration. Overall, 62 is a valuable chemical tool to degrade AKT in cells harboring KRAS/BRAF mutation and expands the tool box for pharmacologically modulating AKT.
UR - http://www.scopus.com/inward/record.url?scp=85139941167&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.2c01454
DO - 10.1021/acs.jmedchem.2c01454
M3 - Article
C2 - 36197750
AN - SCOPUS:85139941167
VL - 65
SP - 14237
EP - 14260
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 20
ER -