Inhibitor Selectivity for Cyclin‐Dependent Kinase 7: A Structural, Thermodynamic, and Modelling Study

Abstract

Table of contents entryWe have solved crystal structures of CDK7--selective inhibitors bound to CDK2.We have used a combination of structural, biophysical and modelling approaches to model the binding of these inhibitors to CDK7, and have used this information to explain their selectivity. We identify specific CDK7 residues that contribute to these inhibitors' specificity. AbstractDeregulation of the cell cycle by mechanisms that lead to elevated activities of cyclin--dependent kinases (CDK) is a feature of many human diseases, in particular cancer. We have identified small molecule inhibitors that selectively inhibit CDK7, the kinase that phosphorylates cell cycle CDKs to promote their activities. To investigate the selectivity of these inhibitors we have used a combination of structural, biophysical and modelling approaches. We have determined crystal structures of the CDK7 selective compounds ICEC0942 and ICEC0943 bound to CDK2, and used these to build models of inhibitor binding to CDK7. Molecular dynamics simulations of inhibitors bound to CDK2 and CDK7 have generated possible models of inhibitor binding. In order to experimentally 3 validate these models, we measured isothermal titration calorimetry (ITC) binding data for recombinant wild type and binding site mutants of CDK7 and CDK2. We have identified specific residues of CDK7, notably Asp155, that are involved in determining inhibitor selectivity. Our molecular dynamics simulations also show that the flexibility of the G--rich and activation loops of CDK7 is likely an important determinant of inhibitor specificity similar to CDK2.4

Therapeutic targeting of transcriptional cyclin-dependent kinases

“…Recently, in silico modeling of BS-181 and related compounds with the crystal structure of CDK7 led to the development of ICEC0942, an analog of BS-181 with improved cell permeability and oral bioavailability [50,51]. ICEC0942 inhibited growth of all NCI-60 cancer cell lines, with a median GI 50 of 0.25 µM [51].…”

Effect of Structural Descriptors on the Design of Cyclin Dependent Kinase Inhibitors Using Similarity‐based Molecular Evolution

“…OMEGA was used to generate up to 200 conformers per compound and provides the multi‐conformer database required for FRED docking. Using the Pdb2Receptor tool, a CDK2 binding pocket was prepared from a co‐crystal structure (PDBID 5JQ5) and the designed molecules were docked to the CDK2 binding pocket. The docking condition was determined by following procedure.…”

CDK7 inhibitors as anticancer drugs

“…A number of selective small molecule inhibitors of CDK7 have been developed. These include the pyrazolopyrimidine derivatives, BS-181 [39] and ICEC0942 [22,107], and the pyrazolotriazine derivatives, LDC4297 [108] and QS1189 [109] (Fig. 3b, Table 3).…”

“…Efforts to develop BS-181 analogues which retain CDK7 selectivity, but have improved drug-like properties, led to the first orally bioavailable CDK7 inhibitor, ICEC0942 (CT7001; Fig. 3b, Table 3) [22,107]. Although crystal structures of CDK7 bound to ICEC0942 could not be obtained, a crystal structure of CDK2 in complex with ICEC0942 was solved [107].…”