Role of aberrant Sonic hedgehog signaling pathway in cancers and developmental anomalies

Patel, Trupti; Dhanyamraju, Pavan Kumar

doi:10.7555/jbr.35.20210139

Cited by 4 publications

(1 citation statement)

References 85 publications

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“…Aberrant activation of Hh/Gli signaling was observed in several human cancers [ 88 , 89 ]. Targeting the Hh/Gli signaling with Smoothened (SMO) inhibitors showed remarkable therapeutic effects in patients with advanced and metastatic basal cell carcinoma [ 41 ].…”

Section: Mirk/dyrk1b Kinase Inhibitorsmentioning

confidence: 99%

Mirk/Dyrk1B Kinase Inhibitors in Targeted Cancer Therapy

Kokkorakis,

Zouridakis,

Gaitanou

2024

Pharmaceutics

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During the last years, there has been an increased effort in the discovery of selective and potent kinase inhibitors for targeted cancer therapy. Kinase inhibitors exhibit less toxicity compared to conventional chemotherapy, and several have entered the market. Mirk/Dyrk1B kinase is a promising pharmacological target in cancer since it is overexpressed in many tumors, and its overexpression is correlated with patients’ poor prognosis. Mirk/Dyrk1B acts as a negative cell cycle regulator, maintaining the survival of quiescent cancer cells and conferring their resistance to chemotherapies. Many studies have demonstrated the valuable therapeutic effect of Mirk/Dyrk1B inhibitors in cancer cell lines, mouse xenografts, and patient-derived 3D-organoids, providing a perspective for entering clinical trials. Since the majority of Mirk/Dyrk1B inhibitors target the highly conserved ATP-binding site, they exhibit off-target effects with other kinases, especially with the highly similar Dyrk1A. In this review, apart from summarizing the data establishing Dyrk1B as a therapeutic target in cancer, we highlight the most potent Mirk/Dyrk1B inhibitors recently reported. We also discuss the limitations and perspectives for the structure-based design of Mirk/Dyrk1B potent and highly selective inhibitors based on the accumulated structural data of Dyrk1A and the recent crystal structure of Dyrk1B with AZ191 inhibitor.

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Section: Mirk/dyrk1b Kinase Inhibitorsmentioning

confidence: 99%

Mirk/Dyrk1B Kinase Inhibitors in Targeted Cancer Therapy

Kokkorakis,

Zouridakis,

Gaitanou

2024

Pharmaceutics

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Hedgehog Signaling in Gonadal Development and Function

Dilower

Niloy

Kumar

et al. 2023

Cells

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Three distinct hedgehog (HH) molecules, (sonic, desert, and indian), two HH receptors (PTCH1 and PTCH2), a membrane bound activator (SMO), and downstream three transcription factors (GLI1, GLI2, and GLI3) are the major components of the HH signaling. These signaling molecules were initially identified in Drosophila melanogaster. Later, it has been found that the HH system is highly conserved across species and essential for organogenesis. HH signaling pathways play key roles in the development of the brain, face, skeleton, musculature, lungs, and gastrointestinal tract. While the sonic HH (SHH) pathway plays a major role in the development of the central nervous system, the desert HH (DHH) regulates the development of the gonads, and the indian HH (IHH) acts on the development of bones and joints. There are also overlapping roles among the HH molecules. In addition to the developmental role of HH signaling in embryonic life, the pathways possess vital physiological roles in testes and ovaries during adult life. Disruption of DHH and/or IHH signaling results in ineffective gonadal steroidogenesis and gametogenesis. While DHH regulates the male gonadal functions, ovarian functions are regulated by both DHH and IHH. This review article focuses on the roles of HH signaling in gonadal development and reproductive functions with an emphasis on ovarian functions. We have acknowledged the original research work that initially reported the findings and discussed the subsequent studies that have further analyzed the role of HH signaling in testes and ovaries.

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Understanding the Roles of the Hedgehog Signaling Pathway during T-Cell Lymphopoiesis and in T-Cell Acute Lymphoblastic Leukemia (T-ALL)

Martelli

Paganelli

Truocchio

et al. 2023

IJMS

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The Hedgehog (HH) signaling network is one of the main regulators of invertebrate and vertebrate embryonic development. Along with other networks, such as NOTCH and WNT, HH signaling specifies both the early patterning and the polarity events as well as the subsequent organ formation via the temporal and spatial regulation of cell proliferation and differentiation. However, aberrant activation of HH signaling has been identified in a broad range of malignant disorders, where it positively influences proliferation, survival, and therapeutic resistance of neoplastic cells. Inhibitors targeting the HH pathway have been tested in preclinical cancer models. The HH pathway is also overactive in other blood malignancies, including T-cell acute lymphoblastic leukemia (T-ALL). This review is intended to summarize our knowledge of the biological roles and pathophysiology of the HH pathway during normal T-cell lymphopoiesis and in T-ALL. In addition, we will discuss potential therapeutic strategies that might expand the clinical usefulness of drugs targeting the HH pathway in T-ALL.

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Role of aberrant Sonic hedgehog signaling pathway in cancers and developmental anomalies

Cited by 4 publications

References 85 publications

Mirk/Dyrk1B Kinase Inhibitors in Targeted Cancer Therapy

Mirk/Dyrk1B Kinase Inhibitors in Targeted Cancer Therapy

Hedgehog Signaling in Gonadal Development and Function

Understanding the Roles of the Hedgehog Signaling Pathway during T-Cell Lymphopoiesis and in T-Cell Acute Lymphoblastic Leukemia (T-ALL)

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