Fragment-Based Drug Discovery of Potent Protein Kinase C Iota Inhibitors

Kwiatkowski, Józef S.; Liu, Boping; Tee, Doris Hui Ying; Chen, Guoying; Ahmad, Nur Huda Binte; Wong, Yun Xuan; Poh, Zhi Ying; Ang, Shi Hua; Tan, Eldwin Sum Wai; Ong, Esther Hq; Dinie, Nurul; Poulsen, Anders; Pendharkar, Vishal; Sangthongpitag, Kanda; Lee, May Ann; Sepramaniam, Sugunavathi; Ho, Soo Yei; Cherian, Joseph; Hill, Jeffrey; Keller, Thomas H.; Hung, Alvin W.

doi:10.1021/acs.jmedchem.8b00060

Cited by 24 publications

(13 citation statements)

References 26 publications

(33 reference statements)

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“…An important study by Kwiatkowski et al identified an azaindole-based scaffold for the development of more potent and specific PKC-ι inhibitors. They described fragmented based approach an introduced a new class of potential aPKC inhibitors based on azaindole [90].…”

Section: Author Detailsmentioning

confidence: 99%

Atypical Protein Kinase Cs in Melanoma Progression

Ratnayake¹,

Apostolatos²,

Acevedo‐Duncan³

2019

Cutaneous Melanoma [Working Title]

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Melanoma is one of the fastest growing types of cancer worldwide in terms of incidence. To date, reports show over 92,000 new cases in the United States in 2018. Previously, we introduced protein kinase C-iota (PKC-ι) as an oncogene in melanoma. PKC-ι promotes survival and cancer progression along with PKCzeta(ζ). In addition, we reported that PKC-ι induced metastasis of melanoma cells by increasing Vimentin dynamics. Our previous results showed that PKC-ι inhibition downregulated epithelial-mesenchymal transition (EMT), while inducing apoptosis. In this chapter, we summarized these findings which were based on the in-vitro applications of five specific atypical PKC (aPKC) inhibitors. In addition, the underlying mechanisms of the transcriptional regulation of PRKCI gene expression in melanoma is also discussed. Results demonstrated that c-Jun promotes PRKCI expression along with Interleukin (IL)-6/8. Furthermore, forkhead box protein O1 (FOXO1) acts as a downregulator of PRKCI expression upon stimulation of IL-17E and intercellular adhesion molecule 1 (ICAM-1) in melanoma cells. Overall, the chapter summarizes the importance of PKC-ι/ζ in the progression of melanoma and discusses the cellular signaling pathways that are altered upon inhibitor applications. Finally, we established that aPKCs are effective novel biomarkers for use in the design of novel targeted therapeutics for melanoma.

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Section: Author Detailsmentioning

confidence: 99%

Atypical Protein Kinase Cs in Melanoma Progression

Ratnayake¹,

Apostolatos²,

Acevedo‐Duncan³

2019

Cutaneous Melanoma [Working Title]

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“…Availability of biochemical or biophysical assays to understand SAR is critical in hit-to-lead step. This strategy has been proven to be successful in numerous targets such as developing bacterial Gyrase B inhibitors (Figure 2; Colony-stimulating factor 1 Computational approach Machiraju et al, 2019 Bruton's Tyrosine Kinase Mass spectrometry Hopkins et al, 2019 The atypical protein kinase C-iota Thermal shift assay Kwiatkowski et al, 2018Kwiatkowski et al, , 2019 Latency-associated nuclear antigen SPR, DSF Kirsch et al, 2019 Monoamine oxidase X-ray crystallography Cheng et al, 2019 Myeloid cell leukemia 1 NMR Murray J.B. et al, 2019;Szlávik et al, 2019 β-ketoacyl-ACP synthases X-ray crystallography Patterson et al, 2020 VEGFR-2 Computational design Zhang et al, 2019 West Nile viral protease STD-NMR Schöne et al, 2017 Transcriptional repressor EthR2…”

Section: Growing Of Fragment Hitsmentioning

confidence: 99%

Application of Fragment-Based Drug Discovery to Versatile Targets

2020

Front. Mol. Biosci.

123

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Fragment-based drug discovery (FBDD) is a powerful method to develop potent smallmolecule compounds starting from fragments binding weakly to targets. As FBDD exhibits several advantages over high-throughput screening campaigns, it becomes an attractive strategy in target-based drug discovery. Many potent compounds/inhibitors of diverse targets have been developed using this approach. Methods used in fragment screening and understanding fragment-binding modes are critical in FBDD. This review elucidates fragment libraries, methods utilized in fragment identification/confirmation, strategies applied in growing the identified fragments into drug-like lead compounds, and applications of FBDD to different targets. As FBDD can be readily carried out through different biophysical and computer-based methods, it will play more important roles in drug discovery.

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“…Heterobiaryl compounds, especially those containing nitrogen, are very important structural units which are widely existed in many pharmaceuticals and biologically active moleculers . Transition‐metal‐catalyzed coupling reactions of aryl halides with heteroaryl organometallic reagents such as heteroaryl zinc reagents, heteroaryl magnesium reagents, heteroaryl aluminum reagents and heteroaryl boron reagents are important ways to construct these compounds.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of heterobiaryls via Suzuki‐Miyaura coupling reaction of potassium aryltrifluoroborates with heteroaryl halides in aqueous systems

Liu

Zhao

et al. 2019

Applied Organom Chemis

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A variety of heterobiaryl compounds have been synthesized by the Suzuki‐Miyaura coupling reactions of heteroaryl halides with potassium aryltrifluoroborates. Pd (OAc)2 was found to be highly efficient for the Suzuki‐Miyaura coupling reactions of various heteroaryl halides with potassium aryltrifluoroborates in aqueous systems, delivering the corresponding heterobiaryl compounds in good to excellent yields.

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Fragment-Based Drug Discovery of Potent Protein Kinase C Iota Inhibitors

Cited by 24 publications

References 26 publications

Atypical Protein Kinase Cs in Melanoma Progression

Atypical Protein Kinase Cs in Melanoma Progression

Application of Fragment-Based Drug Discovery to Versatile Targets

Synthesis of heterobiaryls via Suzuki‐Miyaura coupling reaction of potassium aryltrifluoroborates with heteroaryl halides in aqueous systems

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