R-547

Docking studies identified interactions of the five selected candidates with crucial residues of CDK3. Global reactivity suggested favourable electronic properties for receptor binding. MD simulations, MM-PBSA and ONIOM revealed stable ligand-receptor interactions and favourable binding energetics. Extended 1200ns simulations of the two hits, CID_11212010 and CID_25211747, demonstrated exceptional stability of CID_25211747 with minimal conformational fluctuation. Additional ONIOM calculations reproduced the strong binding affinity of CID_25211747 with CDK3. Collectively, these results nominate CID_25211747 as a promising lead towards the development of effective CDK3 antagonists, offering valuable insight for future drug design.

We confirmed the potential importance of cell cycle-mediated regulation of C/EBPδ by showing that four of the most potent C/EBPδ activators-R547, PHA793387, AZD5438 and AT7519, all multi-cyclin-dependent kinase (CDK) inhibitors-limited the clonal expansion of PDAC cells. Next to providing a valuable selection of C/EBPδ-modulating compounds for the use in preclinical studies, this report contributes to our understanding of the molecular regulatory mechanisms of C/EBPδ in general and in PDAC in particular.

Multiple associations indicate potential epigenetic mechanisms affecting SCLC response to chemotherapy and suggest targets for combination therapies. While many correlations were not specific to SCLC lineages, several lineage markers were associated with specific agents.

Increased methylation and low expression of TREX1 were associated with SCLC cell line sensitivity to multiple Aurora kinase inhibitors AZD-1152, SCH-1473759, SNS-314, and TAK-901, as well as to the CDK inhibitor R-547, Vertex ATR inhibitor Cpd 45, and the mitotic spindle disruptor vinorelbine...Among other examples, EPAS1 (HIF2A) was associated with several Aurora kinase inhibitors, the PLK1 inhibitor GSK-461364, and the Bcl-2 inhibitor ABT-737...IGFBP5, which is expressed in the tuft cell-like SCLC subtype, was associated with the mTOR inhibitor INK-128...Methylation and expression of YAP1, a SCLC lineage driver regulating the Hippo pathway, were correlated with the MTOR inhibitor rapamycin...The 5’ UTR region of the epigenetic modifier EZH2 was associated with Aurora kinase inhibitors and the FGFR inhibitor BGJ-398. These and multiple other associations identified in this study provide a novel understanding of epigenetic mechanisms which may modulate SCLC response to chemotherapy, and suggest potential molecular targets for combination therapies. This research was supported in part with federal funds from the National Cancer Institute, NIH, under contract HHSN261200800001E.