Cyclin dependent kinase 9 (CDK9), a key regulator of transcriptional elongation, is a promising target for cancer therapy, particularly for cancers driven by transcriptional dysregulation. Here, we report the characterization of NVP-2 (3), a selective ATP-competitive CDK9 inhibitor; and THAL-SNS-032, a selective CDK9 degrader consisting of a CDK-binding SNS-032 ligand linked to a thalidomide derivative which binds the E3 ubiquitin ligase Cereblon (CRBN). Surprisingly, THAL-SNS-032 induces rapid degradation of CDK9 without affecting the levels of other SNS-032 targets. Moreover, the transcriptional changes elicited by THAL-SNS-032 were more like those caused by NVP-2 than those induced by SNS-032. Strikingly, compound washout did not significantly reduce levels of THAL-SNS-032-induced apoptosis, suggesting that CDK9 degradation had prolonged cytotoxic effects compared to CDK9 inhibition. Thus, our findings demonstrate thalidomide conjugation represents a promising strategy for converting multi-targeted inhibitors into selective degraders, and reveal that kinase degradation can induce distinct pharmacological effects compared to inhibition.

Women's political representation, once considered unacceptable by politicians and their publics, is now actively encouraged by powerful international actors. In this article, the authors ask how the growth and discourse of the international women's movement affected women's acquisition of political power over time. To answer this question, they use event history techniques to address women's political representation in more than 150 countries over 110 years (1893–2003). They consider multiple political outcomes: female suffrage, first female parliamentarian, and achievement of 10, 20, and 30 percent women in a country's national legislature. The findings show that increasing global pressure for the inclusion of women in international politics and the changing discourse of the international women's movement help to explain women's acquisition of these multiple political outcomes. Furthermore, by adding these concepts to traditional domestic models of women in politics, the authors demonstrate that country-level political, social structural, and cultural characteristics cause countries to act in conjunction with, or in opposition to, these global pressures. This is the first time that research on women in politics has considered such a comprehensive list of countries, time points, and outcomes.

Ror proteins are a conserved family of tyrosine kinase receptors that function in developmental processes, including skeletal and neuronal development, cell movement, and cell polarity. While Ror (receptor tyrosine kinase-like orphan receptor) proteins were originally named because the associated ligand and signaling pathway were unknown, recent studies in multiple species now establish that Ror proteins are Wnt receptors. Depending on the cellular context, Ror proteins can either activate or repress transcription of Wnt target genes and can modulate Wnt signaling by sequestering Wnt ligands. New evidence implicates Ror proteins in planar cell polarity (PCP), an alternative Wnt pathway. Here, we review the progress made in understanding these mysterious proteins and in particular we focus on their function as Wnt receptors.

Summary The orientation of asymmetric cell division contributes to the organization of cells within a tissue or organ. For example, mirror-image symmetry of the C. elegans vulva is achieved by the opposite division orientation of the vulval precursor cells (VPCs) flanking the axis of symmetry. We characterized the molecular mechanisms contributing to this division pattern. Wnts MOM-2 and LIN-44 are expressed at the axis of symmetry and orient the VPCs towards the center. These Wnts act via Fz/LIN-17 and Ryk/LIN-18, which control β-catenin localization and activate gene transcription. In addition, VPCs on both sides of the axis of symmetry possess a uniform underlying “ground” polarity, established by the instructive activity of Wnt/egl-20. EGL-20 establishes ground polarity via a novel type of signaling involving the Ror receptor tyrosine kinase CAM-1 and the Planar Cell Polarity component Van Gogh/VANG-1. Thus, tissue polarity is determined by the integration of multiple Wnt pathways.