A comprehensive insight on the recent development of Cyclic Dependent Kinase inhibitors as anticancer agents

Marak, Brilliant N.; Dowarah, Jayanta; Khiangte, Laldingluaia; Singh, Ved Prakash

doi:10.1016/j.ejmech.2020.112571

Cited by 39 publications

(20 citation statements)

References 164 publications

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“…Furthermore, SMO-independent noncanonical signaling can also influence proliferation and cell cycle regulation in some cell types, notably cerebellar granule precursor cells, which may give rise to medulloblastoma through GLI1-mediated induction of n-myc and Cyclin D1 [82][83][84][85][86]. The cyclin protein family acts as regulatory subunits for cyclin-dependent kinases, which are responsible for regulating cell cycle progression by directly affecting a cell's transcriptional landscape [87]. Specifically involved in traversing the G2/M checkpoint, activated Cyclin B1-Cdk1, essential for mitotic progression, can be regulated by noncanonical SHH signaling [88].…”

Section: Type I-ptch1 Functions Distinct From Smo Inhibitionmentioning

confidence: 99%

Hedgehog Signaling and Truncated GLI1 in Cancer

Doheny

Manore

Wong

et al. 2020

Cells

128

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The hedgehog (HH) signaling pathway regulates normal cell growth and differentiation. As a consequence of improper control, aberrant HH signaling results in tumorigenesis and supports aggressive phenotypes of human cancers, such as neoplastic transformation, tumor progression, metastasis, and drug resistance. Canonical activation of HH signaling occurs through binding of HH ligands to the transmembrane receptor Patched 1 (PTCH1), which derepresses the transmembrane G protein-coupled receptor Smoothened (SMO). Consequently, the glioma-associated oncogene homolog 1 (GLI1) zinc-finger transcription factors, the terminal effectors of the HH pathway, are released from suppressor of fused (SUFU)-mediated cytoplasmic sequestration, permitting nuclear translocation and activation of target genes. Aberrant activation of this pathway has been implicated in several cancer types, including medulloblastoma, rhabdomyosarcoma, basal cell carcinoma, glioblastoma, and cancers of lung, colon, stomach, pancreas, ovarian, and breast. Therefore, several components of the HH pathway are under investigation for targeted cancer therapy, particularly GLI1 and SMO. GLI1 transcripts are reported to undergo alternative splicing to produce truncated variants: loss-of-function GLI1ΔN and gain-of-function truncated GLI1 (tGLI1). This review covers the biochemical steps necessary for propagation of the HH activating signal and the involvement of aberrant HH signaling in human cancers, with a highlight on the tumor-specific gain-of-function tGLI1 isoform.

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Section: Type I-ptch1 Functions Distinct From Smo Inhibitionmentioning

confidence: 99%

Hedgehog Signaling and Truncated GLI1 in Cancer

Doheny

Manore

Wong

et al. 2020

Cells

128

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“…The indole-based hybrids were used as one of the successful strategies to discover potent novel antitumor agents, and the kinases such as CDKs were one of the main targets of these hybrids (Fig. 1 ) [ 19 , 20 ]. It was also reported that the indole-containing hybrid compounds were shown inhibitory activity on CDK1 with IC 50 1.14 µM [ 21 ], significant antiproliferative activities on various kinds of cancer cell lines [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of novel indole-isoxazole hybrids and evaluation of their cytotoxic activities on hepatocellular carcinoma cell lines

et al. 2021

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Background Liver cancer is predicted to be the sixth most diagnosed cancer globally and fourth leading cause of cancer deaths. In this study, a series of indole-3-isoxazole-5-carboxamide derivatives were designed, synthesized, and evaluated for their anticancer activities. The chemical structures of these of final compounds and intermediates were characterized by using IR, HRMS, 1H-NMR and 13C-NMR spectroscopy and element analysis. Results The cytotoxic activity was performed against Huh7, MCF7 and HCT116 cancer cell lines using sulforhodamine B assay. Some compounds showed potent anticancer activities and three of them were chosen for further evaluation on liver cancer cell lines based on SRB assay and real-time cell growth tracking analysis. Compounds were shown to cause arrest in the G0/G1 phase in Huh7 cells and caused a significant decrease in CDK4 levels. A good correlation was obtained between the theoretical predictions of bioavailability using Molinspiration calculation, Lipinski’s rule of five, and experimental verification. These investigations reveal that indole-isoxazole hybrid system have the potential for the development of novel anticancer agents. Conclusions This study has provided data that will form the basis of further studies that aim to optimize both the design and synthesis of novel compounds that have higher anticancer activities.

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“…The adverse side effects are often associated with small molecule inhibitors as their competitive inhibition behavior often leads to off-target activities. Moreover, prolonged exposure to small molecule inhibitors can also influence the mutation of target proteins, which may give rise to drug resistance [265] . Further, prolonged inhibition may promote compensatory protein overexpression and protein accumulation, thereby depleting the target protein only partially and causing incomplete suppression of downstream signaling pathways.…”

Section: Perspective and Conclusionmentioning

confidence: 99%