Therapeutic targeting of PIM KINASE signaling in cancer therapy: Structural and clinical prospects.
Anticancer therapy
Cell signaling
Drug target
Kinase inhibitors
PIM kinase
Protein network
Structural genomics
Journal
Biochimica et biophysica acta. General subjects
ISSN: 1872-8006
Titre abrégé: Biochim Biophys Acta Gen Subj
Pays: Netherlands
ID NLM: 101731726
Informations de publication
Date de publication:
11 2021
11 2021
Historique:
received:
25
05
2021
revised:
28
07
2021
accepted:
23
08
2021
pubmed:
30
8
2021
medline:
17
11
2021
entrez:
29
8
2021
Statut:
ppublish
Résumé
PIM kinases are well-studied drug targets for cancer, belonging to Serine/Threonine kinases family. They are the downstream target of various signaling pathways, and their up/down-regulation affects various physiological processes. PIM family comprises three isoforms, namely, PIM-1, PIM-2, and PIM-3, on alternative initiation of translation and they have different levels of expression in different types of cancers. Its structure shows a unique ATP-binding site in the hinge region which makes it unique among other kinases. PIM kinases are widely reported in hematological malignancies along with prostate and breast cancers. Currently, many drugs are used as inhibitors of PIM kinases. In this review, we highlighted the physiological significance of PIM kinases in the context of disease progression and therapeutic targeting. We comprehensively reviewed the PIM kinases in terms of their expression and regulation of different physiological roles. We further predicted functional partners of PIM kinases to elucidate their role in the cellular physiology of different cancer and mapped their interaction network. A deeper mechanistic insight into the PIM signaling involved in regulating different cellular processes, including transcription, apoptosis, cell cycle regulation, cell proliferation, cell migration and senescence, is provided. Furthermore, structural features of PIM have been dissected to understand the mechanism of inhibition and subsequent implication of designed inhibitors towards therapeutic management of prostate, breast and other cancers. Being a potential drug target for cancer therapy, available drugs and PIM inhibitors at different stages of clinical trials are discussed in detail.
Sections du résumé
BACKGROUND
PIM kinases are well-studied drug targets for cancer, belonging to Serine/Threonine kinases family. They are the downstream target of various signaling pathways, and their up/down-regulation affects various physiological processes. PIM family comprises three isoforms, namely, PIM-1, PIM-2, and PIM-3, on alternative initiation of translation and they have different levels of expression in different types of cancers. Its structure shows a unique ATP-binding site in the hinge region which makes it unique among other kinases.
SCOPE OF REVIEW
PIM kinases are widely reported in hematological malignancies along with prostate and breast cancers. Currently, many drugs are used as inhibitors of PIM kinases. In this review, we highlighted the physiological significance of PIM kinases in the context of disease progression and therapeutic targeting. We comprehensively reviewed the PIM kinases in terms of their expression and regulation of different physiological roles. We further predicted functional partners of PIM kinases to elucidate their role in the cellular physiology of different cancer and mapped their interaction network.
MAJOR CONCLUSIONS
A deeper mechanistic insight into the PIM signaling involved in regulating different cellular processes, including transcription, apoptosis, cell cycle regulation, cell proliferation, cell migration and senescence, is provided. Furthermore, structural features of PIM have been dissected to understand the mechanism of inhibition and subsequent implication of designed inhibitors towards therapeutic management of prostate, breast and other cancers.
GENERAL SIGNIFICANCE
Being a potential drug target for cancer therapy, available drugs and PIM inhibitors at different stages of clinical trials are discussed in detail.
Identifiants
pubmed: 34455019
pii: S0304-4165(21)00154-9
doi: 10.1016/j.bbagen.2021.129995
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
Protein Kinase Inhibitors
0
Proto-Oncogene Proteins c-pim-1
EC 2.7.11.1
proto-oncogene proteins pim
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
129995Informations de copyright
Copyright © 2021 Elsevier B.V. All rights reserved.