cdk7 inhibitor ldc4297  (MedChemExpress)

Journal: Pharmaceutics

Article Title: An Antiherpesviral Host-Directed Strategy Based on CDK7 Covalently Binding Drugs: Target-Selective, Picomolar-Dose, Cross-Virus Reactivity

doi: 10.3390/pharmaceutics16020158

Figure Lengend Snippet: Use of the selective CDK7 inhibitor LDC4297 as the source for generation of novel covalently binding CDK7-directed warheads. ( A ) Chemical linkage of an acceptor for the Michael 1,4 addition reaction was performed to generate QRS compounds 6, 7, and 9. Through the covalent binding of host target CDK7, a block of virus-supportive functions was achieved, and further details on this antiviral strategy were described elsewhere (a,b ; c,d, this study, and Yu et al., in preparation; d–f [ , ]; f–h [ , ]). ( B ) Determination of in vitro eADME parameters (early adsorption-distribution-metabilism-excretion) and pharmacokinetics (PK) parameters, including mean plasma concentrations in vivo (male CD-1 ® mice). For intraperitoneal (i.p.) in vivo applications, the vehicles 30% HP-β-cyclodextrin or 5% Transcutol proved to be most suitable.

Article Snippet: The synthesis and antiviral characterization of the parental, selective CDK7 inhibitor LDC4297 (Lead Discovery Center GmbH, Dortmund, Germany) have previously been described in detail [ , , , , , , ].

Techniques: Binding Assay, Blocking Assay, Virus, In Vitro, Adsorption, Drug discovery, Clinical Proteomics, In Vivo

Journal: Pharmaceutics

Article Title: An Antiherpesviral Host-Directed Strategy Based on CDK7 Covalently Binding Drugs: Target-Selective, Picomolar-Dose, Cross-Virus Reactivity

doi: 10.3390/pharmaceutics16020158

Figure Lengend Snippet: First level of antiviral screening to nominate QRS6, QRS7, and QRS9. Primary human fibroblasts (HFFs) were cultivated in a 12 well format and used for antiviral screening rounds with the HCMV GFP-based replication assay. Infection was performed at an MOI of 0.25 GFP-FU/mL for 7 days (d) before the cells were harvested and the total lysates were used for measurements of automated GFP fluorometry in quadruplicate (infection in duplicates and GFP signal quantitation in duplicates). Note that a representative series of chemically diverse QRS compounds (labeled as Q#) out of a larger number of screening entities is shown, and specifically QRS6, QRS7, and QRS9 of the type of CDK7 covalently binding compounds were identified as the hits exerting a strong anti-HCMV in vitro activity. GCV = ganciclovir reference drug; DMSO = solvent control; mock-inf. = uninfected HFFs as negative control.

Article Snippet: The synthesis and antiviral characterization of the parental, selective CDK7 inhibitor LDC4297 (Lead Discovery Center GmbH, Dortmund, Germany) have previously been described in detail [ , , , , , , ].

Techniques: Infection, Quantitation Assay, Labeling, Binding Assay, In Vitro, Activity Assay, Solvent, Control, Negative Control

Journal: Pharmaceutics

Article Title: An Antiherpesviral Host-Directed Strategy Based on CDK7 Covalently Binding Drugs: Target-Selective, Picomolar-Dose, Cross-Virus Reactivity

doi: 10.3390/pharmaceutics16020158

Figure Lengend Snippet: LANCE Ultra CDK-specific in vitro kinase assay a .

Article Snippet: The synthesis and antiviral characterization of the parental, selective CDK7 inhibitor LDC4297 (Lead Discovery Center GmbH, Dortmund, Germany) have previously been described in detail [ , , , , , , ].

Techniques: In Vitro, Kinase Assay

Journal: Pharmaceutics

Article Title: An Antiherpesviral Host-Directed Strategy Based on CDK7 Covalently Binding Drugs: Target-Selective, Picomolar-Dose, Cross-Virus Reactivity

doi: 10.3390/pharmaceutics16020158

Figure Lengend Snippet: Pronounced antiviral efficacy of the selected CDK7 inhibitor hits QRS6 ( A ), QRS7 ( B ), and QRS9 ( C ) against HCMV in primary human fibroblasts. EC 50 , CC 50 , and SI values were determined by the HCMV GFP-based replication assay, using HFFs in a 12 well format infected at an MOI of 0.25 GFP-FU/mL for 7 d and using measurements of automated GFP fluorometry as performed in quadruplicate (infection in duplicates and GFP signal quantitation in duplicates).

Article Snippet: The synthesis and antiviral characterization of the parental, selective CDK7 inhibitor LDC4297 (Lead Discovery Center GmbH, Dortmund, Germany) have previously been described in detail [ , , , , , , ].

Techniques: Infection, Quantitation Assay