Furo[3,2-b]pyridine: A Privileged Scaffold for Highly Selective Kinase Inhibitors and Effective Modulators of the Hedgehog Pathway

NĚMEC, Václav, Michaela HYLSOVÁ, Lukáš MAIER, Jana FLEGEL, Sonja SIEVERS, Slava ZIEGLER, Martin SCHRÖDER, Benedict-Tilman BERGER, Apirat CHAIKUAD, Barbora VALČÍKOVÁ, Stjepan ULDRIJAN, Stanislav DRÁPELA, Karel SOUČEK, Hebert WALDMANN, Stefan KNAPP and Kamil PARUCH. Furo[3,2-b]pyridine: A Privileged Scaffold for Highly Selective Kinase Inhibitors and Effective Modulators of the Hedgehog Pathway. Angewandte Chemie International Edition. Weinheim: Wiley-VCH, 2019, vol. 58, No 4, p. 1062-1066. ISSN 1433-7851. Available from: https://dx.doi.org/10.1002/anie.201810312.

Basic information

• Original name: Furo[3,2-b]pyridine: A Privileged Scaffold for Highly Selective Kinase Inhibitors and Effective Modulators of the Hedgehog Pathway
• Authors: NĚMEC, Václav (203 Czech Republic, belonging to the institution), Michaela HYLSOVÁ (203 Czech Republic, belonging to the institution), Lukáš MAIER (203 Czech Republic, belonging to the institution), Jana FLEGEL (276 Germany), Sonja SIEVERS (276 Germany), Slava ZIEGLER (276 Germany), Martin SCHRÖDER (276 Germany), Benedict-Tilman BERGER (276 Germany), Apirat CHAIKUAD (764 Thailand), Barbora VALČÍKOVÁ (203 Czech Republic, belonging to the institution), Stjepan ULDRIJAN (203 Czech Republic, belonging to the institution), Stanislav DRÁPELA (203 Czech Republic), Karel SOUČEK (203 Czech Republic), Hebert WALDMANN (276 Germany), Stefan KNAPP (276 Germany) and Kamil PARUCH (203 Czech Republic, guarantor, belonging to the institution).
• Edition: Angewandte Chemie International Edition, Weinheim, Wiley-VCH, 2019, 1433-7851.

Other information

• Original language: English
• Type of outcome: Article in a journal
• Field of Study: 10400 1.4 Chemical sciences
• Country of publisher: Germany
• Confidentiality degree: is not subject to a state or trade secret
• WWW: URL
• Impact factor: Impact factor: 12.959
• RIV identification code: RIV/00216224:14310/19:00109101
• Organization unit: Faculty of Science
• Doi: http://dx.doi.org/10.1002/anie.201810312
• UT WoS: 000456260200017
• Keywords in English: biological activity; chemical probes; heterocycles; inhibitors; kinases
• Tags: 14110513, podil, rivok
• Tags: International impact, Reviewed

Abstract

Reported is the identification of the furo[3,2-b]pyridine core as a novel scaffold for potent and highly selective inhibitors of cdc-like kinases (CLKs) and efficient modulators of the Hedgehog signaling pathway. Initially, a diverse target compound set was prepared by synthetic sequences based on chemoselective metal-mediated couplings, including assembly of the furo[3,2-b]pyridine scaffold by copper-mediated oxidative cyclization. Optimization of the subseries containing 3,5-disubstituted furo[3,2-b]pyridines afforded potent, cell-active, and highly selective inhibitors of CLKs. Profiling of the kinase-inactive subset of 3,5,7-trisubstituted furo[3,2-b]pyridines revealed sub-micromolar modulators of the Hedgehog pathway.

Links

• EF16_025/0007381, research and development project: Name: Preklinická progrese nových organických sloučenin s cílenou biologickou aktivitou
• LM2015063, research and development project: Name: Národní infrastruktura chemické biologie (Acronym: CZ-­OPENSCREEN)

Investor: Ministry of Education, Youth and Sports of the CR

• MUNI/A/1087/2018, interní kód MU: Name: Molekulární a buněčná biologie pro biomedicínské vědy

Investor: Masaryk University, Category A

• MUNI/E/0456/2018, interní kód MU: Name: Finální profilace vysoce účinných a selektivních inhibitorů proteinových kináz CLK a CK1

Investor: Masaryk University, Promoting quality excellence