Synthesis and structure–activity relationships of soluble 8-substituted 4-(2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones as inhibitors of the Wee1 and Chk1 checkpoint kinases

Smaill, Jeff B.; Lee, Ho H.; Palmer, Brian D.; Thompson, A. M.; Squire, C.J.; Baker, Edward N.; Booth, Roger J.; Kraker, Alan J.; Hook, Ken; Denny, William A.

doi:10.1016/j.bmcl.2007.12.046

Cited by 27 publications

(16 citation statements)

References 7 publications

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“…By contrast, the interaction of MK-1775 with Myt1 showed unfavorable entropy changes resulting in significantly weaker binding affinity ( K d = 320 nM). Previously known X-ray crystal structures of Wee kinases were those of Wee1 liganded with one series of pyrrolo-carbazole inhibitors 27,28 and of unliganded Myt1 (PDB entry 3P1A). We therefore determined high-resolution X-ray cocrystal structures of the kinase domains of all three Wee kinases with MK-1775 (Figure 2, Supporting Information Figures S4–S6 and Tables S3–S4).…”

Section: Resultsmentioning

confidence: 99%

Structural Basis of Wee Kinases Functionality and Inactivation by Diverse Small Molecule Inhibitors

et al. 2017

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Members of the Wee family of kinases negatively regulate the cell cycle via phosphorylation of CDK1 and are considered potential drug targets. Herein, we investigated the structure–function relationship of human Wee1, Wee2, and Myt1 (PKMYT1). Purified recombinant full-length proteins and kinase domain constructs differed substantially in phosphorylation states and catalytic competency, suggesting complex mechanisms of activation. A series of crystal structures reveal unique features that distinguish Wee1 and Wee2 from Myt1 and establish the structural basis of differential inhibition by the widely used Wee1 inhibitor MK-1775. Kinome profiling and cellular studies demonstrate that, in addition to Wee1 and Wee2, MK-1775 is an equally potent inhibitor of the polo-like kinase PLK1. Several previously unrecognized inhibitors of Wee kinases were discovered and characterized. Combined, the data provide a comprehensive view on the catalytic and structural properties of Wee kinases and a framework for the rational design of novel inhibitors thereof.

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Section: Resultsmentioning

confidence: 99%

Structural Basis of Wee Kinases Functionality and Inactivation by Diverse Small Molecule Inhibitors

et al. 2017

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“…30,31,37 These analogs allowed us to investigate the inhibition by a set of compounds comprising two scaffolds ( 1 and 2 , see Table 1), both closely related to our initial hit 1a . Therefore, we used analogs of 1a to evaluate if this compound class is a useful starting point for finding inhibitors of the IM complex.…”

Section: Resultsmentioning

confidence: 99%

Validation of inhibitors of an ABC transporter required to transport lipopolysaccharide to the cell surface in Escherichia coli

Sherman

Okuda

Denny

et al. 2013

Bioorganic & Medicinal Chemistry

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The presence of lipopolysaccharide (LPS) in the outer leaflet of the outer membrane (OM) of Gram-negative bacteria creates a permeability barrier that prevents the entry of most currently available antibiotics. The seven lipopolysaccharide transport (Lpt) proteins involved in transporting and assembling this glycolipid are essential for growth and division in Escherichia coli; therefore, inhibiting their functions leads to cell death. LptB, the ATPase that provides energy for LPS transport and assembly, forms a complex with three other inner membrane (IM) components, LptC, F, and G. We demonstrate that inhibitors of pure LptB can also inhibit the full IM complex, LptBFGC, purified in detergent. We also compare inhibition of LptB and the LptBFGC complex with the antibiotic activity of these compounds. Our long-term goal is to develop tools to study inhibitors of LPS biogenesis that could serve as potentiators by disrupting the OM permeability barrier, facilitating entry of clinically used antibiotics not normally used to treat Gram-negative infections, or that can serve as antibiotics themselves.

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“…A number of small molecule compounds can inhibit WEE1, by down-regulating CDK1 phosphorylation [77][78][79][80]. Preliminary results of early-stage clinical trials with MK1775 have been recently reported, showing the feasibility of the combination [81].…”

Section: Wee1 and Cell Cycle Controlmentioning

confidence: 96%

Treatment of metastatic cervical cancer: Future directions involving targeted agents

Díaz-Padilla

Monk

Mackay

et al. 2013

Critical Reviews in Oncology/Hematology

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Synthesis and structure–activity relationships of soluble 8-substituted 4-(2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones as inhibitors of the Wee1 and Chk1 checkpoint kinases

Cited by 27 publications

References 7 publications

Structural Basis of Wee Kinases Functionality and Inactivation by Diverse Small Molecule Inhibitors

Structural Basis of Wee Kinases Functionality and Inactivation by Diverse Small Molecule Inhibitors

Validation of inhibitors of an ABC transporter required to transport lipopolysaccharide to the cell surface in Escherichia coli

Treatment of metastatic cervical cancer: Future directions involving targeted agents

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