The Pyrazolobenzothiazine Core as a New Chemotype of p38 Alpha Mitogen‐Activated Protein Kinase Inhibitors

Sabatini, Stefano; Manfroni, Giuseppe; Barreca, Maria Letizia; Bauer, Silke M.; Gargaro, Marco; Cannalire, Rolando; Astolfi, Andrea; Brea, José; Vacca, Carmine; Pirro, Matteo; Massari, Serena; Tabarrini, Oriana; Loza, Marı́a Isabel; Fallarino, Francesca; Laufer, Stefan; Cecchetti, Violetta

doi:10.1111/cbdd.12516

Cited by 14 publications

(6 citation statements)

References 49 publications

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“…3c-e) and in accordance with the literature. 30,31 Together, this supports the biological effect of Pyr-2 observed using human skin explants, following UV-irradiation.…”

Section: Docking Analysis Supporting the Bioactive Interaction Of Pyr...supporting

confidence: 78%

Integrating targeted gene expression and a skin model system to identify functional inhibitors of the UV activated p38 MAP kinase

Abrahams

Mouchet

Gouault

et al. 2016

Photochem Photobiol Sci

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The stress-activated p38α MAP Kinase is an integral and critical component of the UV-induced inflammatory response. Despite the advances in recent years in the development of p38 kinase inhibitors, validation of these compounds in the diseased models remains limited. Based on the pharmacological profile of p38α inhibitor lead compound, SB203580, we synthesized a series of pyrrole-derivatives. Using UV-irradiated human skin punch-biopsies and cell cultures, we identified and validated the inhibitory activity of the derivatives by quantitatively measuring their effect on the expression of p38α target genes using real-time PCR. This approach not only identified pyrrole-2 as a unique derivative of this series that specifically inhibited the UV-activated p38α kinase, but also documented the skin permeation, bioavailability and reversible properties of this derivative in a 3D structure. The successful skin permeation of pyrrole-2 and its impact on AREG, COX-2 and MMP-9 gene expression demonstrates its potential use in modulating inflammatory processes in the skin. This study underscored the importance of using adapted biological models to identify accurate bioactive compounds.

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“…3c-e) and in accordance with the literature. 30,31 Together, this supports the biological effect of Pyr-2 observed using human skin explants, following UV-irradiation.…”

Section: Docking Analysis Supporting the Bioactive Interaction Of Pyr...supporting

confidence: 78%

Integrating targeted gene expression and a skin model system to identify functional inhibitors of the UV activated p38 MAP kinase

Abrahams

Mouchet

Gouault

et al. 2016

Photochem Photobiol Sci

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“…Sabatini et al 173 developed a series of pyrazolam benzothiazide p38α selective inhibitors in 2015, in which compound 78 had an IC 50 of 0.457 μM against p38α and 0.5 μM against TNF‐α. In addition, the IC 50 of p38β was 1.7 μM, while the inhibitory effect on other kinases such as CDC2, CDK5, JAK2/3, Lck, and SRC was not detected.…”

Section: P38mapk Small Molecule Inhibitorsmentioning

confidence: 99%

p38 mitogen‐activated protein kinase: Functions and targeted therapy in diseases

Zheng,

Li,

Wang

et al. 2023

MedComm – Oncology

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P38 mitogen‐activated protein kinase (p38MAPK) is a multifunctional protein kinase that plays an important role in human normal physiological activities and a variety of major diseases, and its signaling pathway affects a variety of regulatory factors in vivo, which is related to cell cycle, survival, metabolism, and differentiation. The four subtypes of p38MAPK have significant differences in their distribution, content, and effects in the body. The inhibitors of the four subtypes play potential roles in regulating cancer, neurodegenerative diseases, inflammation, and cardiovascular diseases, making it an attractive target for drug development. So far, an increasing number of p38MAPK inhibitors have been developed for targeted therapy in diseases, among which some representative compounds have entered clinical trials. Therefore, this review aims to provide a summary of the structural characteristics, signaling pathways of P38MAPK and the relationship between p38MAPK and disease, along with an overview of the binding modes and structure–activity relationships of small molecule inhibitors targeting four p38MAPK subtypes, and summarizes the challenges about the development of p38MAPK inhibitors, hoping to provide a valuable reference for the development and application of novel inhibitors.

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“…Interestingly, a data literature search using SciFinder [42] pointed out that neither compound T187 nor its chemical scaffold N- (5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophen-2-yl)benzamide had ever been investigated in the context of AKT1 inhibition. Intrigued by these results and stimulated by our interest and expertise in the field of kinases [43][44][45] and AML [46][47][48], we decided to take advantage of the serendipitous discovery of T187 to rationally search for other AKT1 inhibitors within our in-house compound library (herein after called UNIPG-lib). Specifically, the UNIPG-lib is a chemical collection of ~3000 small molecules, including both target compounds and intermediates, synthesized and/or collected by the research team in the context of several drug discovery projects.…”

Section: Computer-aided Identification Of Novel Akt1 Inhibitorsmentioning

confidence: 99%

From Serendipity to Rational Identification of the 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one Core as a New Chemotype of AKT1 Inhibitors for Acute Myeloid Leukemia

et al. 2022

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Acute myeloid leukemia (AML) is a heterogeneous hematopoietic malignancy whose prognosis is globally poor. In more than 60% of AML patients, the PI3K/AKTs/mTOR signaling pathway is aberrantly activated because of oncogenic driver alterations and further enhanced by chemotherapy as a mechanism of drug resistance. Against this backdrop, very recently we have started a multidisciplinary research project focused on AKT1 as a pharmacological target to identify novel anti-AML agents. Indeed, the serendipitous finding of the in-house compound T187 as an AKT1 inhibitor has paved the way to the rational identification of new active small molecules, among which T126 has emerged as the most interesting compound with IC50 = 1.99 ± 0.11 μM, ligand efficiency of 0.35, and a clear effect at low micromolar concentrations on growth inhibition and induction of apoptosis in AML cells. The collected results together with preliminary SAR data strongly indicate that the 5,6,7,8-tetrahydrobenzo [4,5]thieno[2,3-d]pyrimidin-4(3H)-one derivative T126 is worthy of future biological experiments and medicinal chemistry efforts aimed at developing a novel chemical class of AKT1 inhibitors as anti-AML agents.

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The Pyrazolobenzothiazine Core as a New Chemotype of p38 Alpha Mitogen‐Activated Protein Kinase Inhibitors

Cited by 14 publications

References 49 publications

Integrating targeted gene expression and a skin model system to identify functional inhibitors of the UV activated p38 MAP kinase

Integrating targeted gene expression and a skin model system to identify functional inhibitors of the UV activated p38 MAP kinase

p38 mitogen‐activated protein kinase: Functions and targeted therapy in diseases

From Serendipity to Rational Identification of the 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one Core as a New Chemotype of AKT1 Inhibitors for Acute Myeloid Leukemia

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