PMID- 37803138
OWN - NLM
STAT- MEDLINE
DCOM- 20240117
LR  - 20240118
IS  - 1745-7254 (Electronic)
IS  - 1671-4083 (Print)
IS  - 1671-4083 (Linking)
VI  - 45
IP  - 2
DP  - 2024 Feb
TI  - Development of PI3Kgamma selective inhibitors: the strategies and application.
PG  - 238-247
LID - 10.1038/s41401-023-01166-8 [doi]
AB  - The gamma isoform of Class I PI3Ks (PI3Kgamma) is primarily found in leukocytes and is 
      essential for the function of myeloid cells, as it regulates the migration, 
      differentiation, and activation of myeloid-lineage immune cells. Thus, PI3Kgamma has 
      been identified as a promising drug target for the treatment of inflammation, 
      autoimmune disease, and immuno-oncology. Due to the high incidence of serious 
      adverse events (AEs) associated with PI3K inhibitors, in the development of PI3Kgamma 
      inhibitors, isoform selectivity was deemed crucial. In this review, an overview 
      of the development of PI3Kgamma selective inhibitors in the past years is provided. 
      The isoform selectivity of related drugs was achieved by different strategies, 
      including inducing a specificity pocket by a propeller-shape structure, targeting 
      steric differences in the solvent channel, and modulating the conformation of the 
      Asp-Phe-Gly DFG motif, which have been demonstrated feasible by several 
      successful cases. The insights in this manuscript may provide a potential 
      direction for rational drug design and accelerate the discovery of PI3Kgamma 
      selective inhibitors.
CI  - (c) 2023. The Author(s), under exclusive licence to Shanghai Institute of Materia 
      Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.
FAU - Gu, Dong-Yan
AU  - Gu DY
AD  - College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
FAU - Zhang, Meng-Meng
AU  - Zhang MM
AD  - National Center for Drug Screening, State Key Laboratory of Drug Research, 
      Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 
      201203, China.
FAU - Li, Jia
AU  - Li J
AD  - National Center for Drug Screening, State Key Laboratory of Drug Research, 
      Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 
      201203, China.
FAU - Zhou, Yu-Bo
AU  - Zhou YB
AD  - National Center for Drug Screening, State Key Laboratory of Drug Research, 
      Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 
      201203, China.
FAU - Sheng, Rong
AU  - Sheng R
AD  - College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. 
      shengr@zju.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Review
DEP - 20231006
PL  - United States
TA  - Acta Pharmacol Sin
JT  - Acta pharmacologica Sinica
JID - 100956087
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Protein Isoforms)
SB  - IM
MH  - Humans
MH  - *Phosphatidylinositol 3-Kinases
MH  - Phosphoinositide-3 Kinase Inhibitors/chemistry
MH  - *Autoimmune Diseases/drug therapy
MH  - Protein Isoforms
MH  - Inflammation/drug therapy
PMC - PMC10789806
OTO - NOTNLM
OT  - PI3K
OT  - PI3Kgamma inhibitors
OT  - drug development
OT  - isoform selectivity
OT  - rational drug design
COIS- The authors declare no competing interests.
EDAT- 2023/10/07 00:42
MHDA- 2024/01/17 06:42
PMCR- 2025/02/01
CRDT- 2023/10/06 23:28
PHST- 2023/06/14 00:00 [received]
PHST- 2023/09/04 00:00 [accepted]
PHST- 2025/02/01 00:00 [pmc-release]
PHST- 2024/01/17 06:42 [medline]
PHST- 2023/10/07 00:42 [pubmed]
PHST- 2023/10/06 23:28 [entrez]
AID - 10.1038/s41401-023-01166-8 [pii]
AID - 1166 [pii]
AID - 10.1038/s41401-023-01166-8 [doi]
PST - ppublish
SO  - Acta Pharmacol Sin. 2024 Feb;45(2):238-247. doi: 10.1038/s41401-023-01166-8. Epub 
      2023 Oct 6.