Palazestrant (OP-1250), A Complete Estrogen Receptor Antagonist, Inhibits Wild-type and Mutant ER-positive Breast Cancer Models as Monotherapy and in Combination.

The estrogen receptor (ER) is a well-established target for the treatment of breast cancer, with the majority of patients presenting as ER-positive (ER+). Endocrine therapy is a mainstay of breast cancer treatment but the development of resistance mutations in response to aromatase inhibitors, poor pharmacokinetic properties of fulvestrant, agonist activity of tamoxifen, and limited benefit for elacestrant leave unmet needs for patients with or without resistance mutations in ESR1, the gene that encodes the ER protein. Here we describe palazestrant (OP-1250), a novel, orally bioavailable complete ER antagonist and selective ER degrader. OP-1250, like fulvestrant, has no agonist activity on the ER and completely blocks estrogen-induced transcriptional activity. In addition, OP-1250 demonstrates favorable biochemical binding affinity, ER degradation, and antiproliferative activity in ER+ breast cancer models that is comparable or superior to other agents of interest. OP-1250 has superior pharmacokinetic properties relative to fulvestrant, including oral bioavailability and brain penetrance, as well as superior performance in wild-type and ESR1-mutant breast cancer xenograft studies. OP-1250 combines well with cyclin-dependent kinase 4 and 6 inhibitors in xenograft studies of ER+ breast cancer models and effectively shrinks intracranially implanted tumors, resulting in prolonged animal survival. With demonstrated preclinical efficacy exceeding fulvestrant in wild-type models, elacestrant in ESR1-mutant models, and tamoxifen in intracranial xenografts, OP-1250 has the potential to benefit patients with ER+ breast cancer.

Genoviz Software Development Kit: Java tool kit for building genomics visualization applications.

BACKGROUND: Visualization software can expose previously undiscovered patterns in genomic data and advance biological science. RESULTS: The Genoviz Software Development Kit (SDK) is an open source, Java-based framework designed for rapid assembly of visualization software applications for genomics. The Genoviz SDK framework provides a mechanism for incorporating adaptive, dynamic zooming into applications, a desirable feature of genome viewers. Visualization capabilities of the Genoviz SDK include automated layout of features along genetic or genomic axes; support for user interactions with graphical elements (Glyphs) in a map; a variety of Glyph sub-classes that promote experimentation with new ways of representing data in graphical formats; and support for adaptive, semantic zooming, whereby objects change their appearance depending on zoom level and zooming rate adapts to the current scale. Freely available demonstration and production quality applications, including the Integrated Genome Browser, illustrate Genoviz SDK capabilities. CONCLUSION: Separation between graphics components and genomic data models makes it easy for developers to add visualization capability to pre-existing applications or build new applications using third-party data models. Source code, documentation, sample applications, and tutorials are available at http://genoviz.sourceforge.net/.