Title:Potential Pharmacological Inhibitors of Pim Kinase Under Clinical Trials
Volume: 18
Issue: 8
Author(s): Gomathi P. Jeyapal, Moola J.N. Chandrasekar*, Rajendiran Krishnasamy, Jubie Selvaraj, Manal Mohammad and Moola J. Nanjan
Affiliation:
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy (A Constituent College of Jagadguru Sri Shivarathreeswara University, Mysuru), Ootacamund-643001, Tamilnadu,India
Keywords:
Pim kinase inhibitors, clinical trials, haematological malignancies, solid cancers, apoptosis, X-ray crystallographic studies.
Abstract: Pim kinases, also known as Serine/Threonine kinases, are intensively studied protein drug targets in
cancer research. They play crucial role in the regulation of signal transduction cascades that promote cell survival,
proliferation and drug resistance. Pim kinases are overexpressed in several hematopoietic and solid tumors
and support in vitro/in vivo malignant cell growth and survival, through cell cycle regulation and inhibition of
apoptosis. Pim kinases do not have an identified regulatory domain, as they are constitutively active. They appear
to be critical downstream effectors of a number of oncoproteins. When overexpressed, they mediate drug
resistance to agents such as Rapamycin. X-ray crystallographic studies reveal that unlike other kinases, Pim
kinases have a hinge region, which forms a unique binding pocket for ATP, offering a target for a large number
of potent small-molecule Pim kinase inhibitors. Combination therapy of Pim kinase inhibitors with chemotherapeutic
and other kinase modulators seems to produce an additive cytotoxic effect in cancer cells. Though clinical
trials have been carried out on the first Pim inhibitory agent, SGI-1776, no concept data could be generated due
to its early withdrawal. However, it has helped in accelerating the discovery of several novel Pim inhibitors in
recent years. Current research on Pim kinase is expected to lead to a new generation of potent Pim kinase inhibitors
with appropriate pharmacological profiles suitable for human cancer therapy in the near future. Herein, we
review the synthetic route and mechanistical studies of Pim kinase inhibitors which are currently in human trials.
