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Characterization at the Molecular Level using Robust Biochemical Approaches of a New Kinase Protein
Published on: June 30, 2019
A review on structure-function mechanism and signaling pathway of serine/threonine protein PIM kinases as a
Ajaya Kumar Rout1, Budheswar Dehury2, Satya Narayan Parida1
1Rani Lakshmi Bai Central Agricultural University, Jhansi-284003, Uttar Pradesh, India.
Abstract:
The proviral integration for the Moloney murine leukemia virus (PIM) kinases, belonging to serine/threonine kinase family, have been found to be overexpressed in various types of cancers, such as prostate, breast, colon, endometrial, gastric, and pancreatic cancer. The three isoforms PIM kinases i.e., PIM1, PIM2, and PIM3 share a high degree of sequence and structural similarity and phosphorylate substrates controlling tumorigenic phenotypes like proliferation and cell survival. Targeting short-lived PIM kinases presents an intriguing strategy as in vivo knock-down studies result in non-lethal phenotypes, indicating that clinical inhibition of PIM might have fewer adverse effects. The ATP binding site (hinge region) possesses distinctive attributes, which led to the development of novel small molecule scaffolds that target either one or all three PIM isoforms. Machine learning and structure-based approaches have been at the forefront of developing novel and effective chemical therapeutics against PIM in preclinical and clinical settings, and none have yet received approval for cancer treatment. The stability of PIM isoforms is maintained by PIM kinase activity, which leads to resistance against PIM inhibitors and chemotherapy; thus, to overcome such effects, PIM proteolysis targeting chimeras (PROTACs) are now being developed that specifically degrade PIM proteins. In this review, we recapitulate an overview of the oncogenic functions of PIM kinases, their structure, function, and crucial signaling network in different types of cancer, and the potential of pharmacological small-molecule inhibitors. Further, our comprehensive review also provides valuable insights for developing novel antitumor drugs that specifically target PIM kinases in the future. In conclusion, we provide insights into the benefits of degrading PIM kinases as opposed to blocking their catalytic activity to address the oncogenic potential of PIM kinases.
Insights
Proviral integration for Moloney murine leukemia virus (PIM) kinases are overexpressed in many cancers. Targeting PIM kinases through degradation, rather than inhibition, offers a promising strategy for novel cancer therapeutics.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Proviral integration for Moloney murine leukemia virus (PIM) kinases are serine/threonine kinases implicated in various cancers, including prostate, breast, and pancreatic cancer.
- PIM kinases (PIM1, PIM2, PIM3) share structural similarities and regulate cell proliferation and survival, contributing to tumorigenesis.
- In vivo studies suggest PIM kinase inhibition may have fewer adverse effects due to their short half-life.
Purpose of the Study:
- To review the oncogenic functions, structure, and signaling networks of PIM kinases in cancer.
- To explore the potential of small-molecule inhibitors and proteolysis targeting chimeras (PROTACs) for PIM kinase-targeted cancer therapy.
- To provide insights into novel antitumor drug development strategies focusing on PIM kinases.
Main Methods:
- Literature review of PIM kinase functions, signaling, and therapeutic targeting strategies.
- Analysis of structure-based and machine learning approaches in developing PIM inhibitors.
- Examination of PIM proteolysis targeting chimeras (PROTACs) as a novel therapeutic modality.
Main Results:
- PIM kinases are overexpressed in multiple cancer types and drive proliferation and survival.
- Small molecule inhibitors targeting PIM kinases have been developed using structure-based and machine learning approaches, but none are approved for cancer treatment.
- PIM kinase activity contributes to resistance against existing therapies, necessitating alternative strategies like PROTACs.
Conclusions:
- Degrading PIM kinases via PROTACs may be more effective than inhibiting their catalytic activity for cancer treatment.
- Targeting PIM kinases, particularly through degradation, represents a promising avenue for developing novel antitumor drugs.
- Further research into PIM kinase biology and therapeutic targeting is crucial for advancing cancer therapy.
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