Molecular profiling and combinatorial activity of CCT068127: a potent CDK2 and CDK9 inhibitor

Deregulation of the cyclin-dependent kinases (CDKs) has been implicated in the pathogenesis of multiple cancer types. Consequently, CDKs have garnered intense interest as therapeutic targets for the treatment of cancer. We describe herein the molecular and cellular effects of CCT068127, a novel inhibitor of CDK2 and CDK9. Optimised from the purine template of seliciclib, CCT068127 exhibits greater potency and selectivity against purified CDK2 and CDK9 and superior antiproliferative activity against human colon cancer and melanoma cell lines. X-ray crystallography studies reveal that hydrogen bonding with the DFG motif of CDK2 is the likely mechanism of greater enzymatic potency. Commensurate with inhibition of CDK activity, CCT068127 treatment results in decreased retinoblastoma protein (RB) phosphorylation, reduced phosphorylation of RNA polymerase II and induction of cell cycle arrest and apoptosis. The transcriptional signature of CCT068127 shows greatest similarity to other small molecule CDK and also HDAC inhibitors. CCT068127 caused a dramatic loss in expression of DUSP6 phosphatase, alongside elevated ERK phosphorylation and activation of MAPK pathway target genes. MCL1 protein levels are rapidly decreased by CCT068127 treatment and this associates with synergistic antiproliferative activity after combined treatment with CCT068127 and ABT263, a BCL2-family inhibitor. These findings support the rational combination of this series of CDK2/9 inhibitors and BCL2 family inhibitors for the treatment of human cancer

The Astropy Project: Building an inclusive, open-science project and status of the v2.0 core package

The Astropy project supports and fosters the development of open-source and openly-developed Python packages that provide commonly-needed functionality to the astronomical community. A key element of the Astropy project is the core package Astropy, which serves as the foundation for more specialized projects and packages. In this article, we provide an overview of the organization of the Astropy project and summarize key features in the core package as of the recent major release, version 2.0. We then describe the project infrastructure designed to facilitate and support development for a broader ecosystem of inter-operable packages. We conclude with a future outlook of planned new features and directions for the broader Astropy project

BH3 Inhibitor Sensitivity and Bcl-2 Dependence in Primary Acute Lymphoblastic Leukemia Cells

Immunobiology of allogeneic stem cell transplantation and immunotherapy of hematological disease