Therapeutic targeting of PIM KINASE signaling in cancer therapy: Structural and clinical prospects,Biochimica et Biophysica Acta (BBA) - General Subjects

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Therapeutic targeting of PIM KINASE signaling in cancer therapy: Structural and clinical prospects
Biochimica et Biophysica Acta (BBA) - General Subjects ( IF 2.8 ) Pub Date : 2021-08-26 , DOI: 10.1016/j.bbagen.2021.129995
Aanchal Rathi ₁ , Dhiraj Kumar ₂ , Gulam Mustafa Hasan ₃ , Mohammad Mahfuzul Haque ₁ , Md Imtaiyaz Hassan ₂

Affiliation

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.

中文翻译：

PIM KINASE 信号在癌症治疗中的靶向治疗：结构和临床前景

背景

PIM 激酶是经过充分研究的癌症药物靶点，属于丝氨酸/苏氨酸激酶家族。它们是各种信号通路的下游目标，它们的上调/下调影响各种生理过程。PIM 家族包含三种同工型，即 PIM-1、PIM-2 和 PIM-3，在翻译的替代起始上，它们在不同类型的癌症中具有不同的表达水平。其结构在铰链区显示出独特的 ATP 结合位点，这使其在其他激酶中独一无二。

审查范围

PIM 激酶在血液系统恶性肿瘤以及前列腺癌和乳腺癌中被广泛报道。目前，许多药物被用作 PIM 激酶的抑制剂。在这篇综述中，我们强调了 PIM 激酶在疾病进展和治疗靶向的背景下的生理意义。我们全面回顾了 PIM 激酶在不同生理作用的表达和调节方面。我们进一步预测了 PIM 激酶的功能伙伴，以阐明它们在不同癌症的细胞生理学中的作用并绘制它们的相互作用网络。