CDK9 inhibition by dinaciclib is a therapeutic vulnerability in epithelioid hemangioendothelioma.

PURPOSE: There are no effective treatment options for patients with aggressive epithelioid hemangioendothelioma (EHE) driven by the TAZ-CAMTA1 (TC) fusion gene. Here, we aimed to understand the regulation of TC using pharmacological tools and identify vulnerabilities that can potentially be exploited for the treatment of EHE. EXPERIMENTAL DESIGN: TC is a transcriptional co-regulator; we hypothesized that compounds that reduce TC nuclear levels, either through translocation of TC to the cytoplasm, or through degradation, would render TC less oncogenic. TC localization was monitored using immunofluorescence (IF) in an EHE tumor cell line. Two target-selective libraries were used to identify small molecules that reduce TC localization in the nucleus. The ability of the shortlisted hits to affect cell viability, apoptosis, and tumorigenesis was also evaluated. RESULTS: Basal TC remained 'immobile' in the nucleus; administration of cyclin-dependent kinase inhibitors (CDKi) such as CGP60474 and dinaciclib mobilized TC. 'Mobile' TC shuttled between the nucleus and cytoplasm; however, it was eventually degraded through proteasomes. This dramatically suppressed the levels of TC-regulated transcripts and cell viability, promoted apoptosis, and reduced the area of metastatic lesions in the allograft model of EHE. We specifically identified that the inhibition of CDK9, a transcriptional CDK, destabilizes TC. CONCLUSIONS: The CDK inhibitor dinaciclib exhibited anti-tumorigenic properties both in vitro and in vivo in EHE models. Dinaciclib has been rigorously tested in clinical trials and displayed an acceptable toxicity profile. Therefore, there is a potential therapeutic window for repurposing dinaciclib for the treatment of EHE.

Association of sildenafil use with age-related macular degeneration: a retrospective cohort study.

OBJECTIVE: Despite significant advances in clinical care and understanding of the underlying pathophysiology, age-related macular degeneration (AMD)-a major cause of global blindness-lacks effective treatment to prevent the irreversible degeneration of photoreceptors leading to central vision loss. Limited studies suggest phosphodiesterase type 5 (PDE5) inhibitors, such as sildenafil, may prevent AMD by increasing retinal blood flow. This study explores the potential association between sildenafil use and AMD risk in men with erectile dysfunction using UK data. METHODS AND ANALYSIS: Using the UK's IQVIA Medical Research Data, the study analysed 31 575 men prescribed sildenafil for erectile dysfunction and no AMD history from 2007 to 2015, matched with a comparator group of 62 155 non-sildenafil users in a 1:2 ratio, over a median follow-up of approximately three years. RESULTS: The primary outcome was the incidence of AMD in the two groups. The study found no significant difference in AMD incidence between the sildenafil users and the non-users, with an adjusted hazard ratio (HR) of 0.99 (95% CI 0.84 to 1.16), after accounting for confounders such as age, ethnicity, Townsend deprivation quintile, body mass index category, and diagnosis of hypertension and type 2 diabetes. CONCLUSION: The study results indicated no significant association between sildenafil use and AMD prevention in UK men with erectile dysfunction, suggesting sildenafil's protective effect on AMD is likely insignificant.

Discovery and Characterization of Selective, First-in-Class Inhibitors of Citron Kinase.

Citron kinase (CITK) is an AGC-family serine/threonine kinase that regulates cytokinesis. Despite knockdown experiments implicating CITK as an anticancer target, no selective CITK inhibitors exist. We transformed a previously reported kinase inhibitor with weak off-target CITK activity into a first-in-class CITK chemical probe, C3TD879. C3TD879 is a Type I kinase inhibitor which potently inhibits CITK catalytic activity (biochemical IC50 = 12 nM), binds directly to full-length human CITK in cells (NanoBRET Kd < 10 nM), and demonstrates favorable DMPK properties for in vivo evaluation. We engineered exquisite selectivity for CITK (>17-fold versus 373 other human kinases), making C3TD879 the first chemical probe suitable for interrogating the complex biology of CITK. Our small-molecule CITK inhibitors could not phenocopy the effects of CITK knockdown in cell proliferation, cell cycle progression, or cytokinesis assays, providing preliminary evidence that the structural roles of CITK may be more important than its kinase activity.