To be or not to be - Decoding the Trabecular Meshwork Cell Identity.

The trabecular meshwork within the conventional outflow apparatus is critical in maintaining intraocular pressure homeostasis. In vitro studies employing primary cell cultures of the human trabecular meshwork (hTM) have conventionally served as surrogates for investigating the pathobiology of TM dysfunction. Despite its abundant use, translation of outcomes from in vitro studies to ex vivo and/or in vivo studies remains a challenge. Given the cell heterogeneity, performing single-cell RNA sequencing comparing primary hTM cell cultures to hTM tissue may provide important insights on cellular identity and translatability, as such an approach has not been reported before. In this study, we assembled a total of 14 primary hTM in vitro samples across passages 1-4, including 4 samples from individuals diagnosed with glaucoma. This dataset offers a comprehensive transcriptomic resource of primary hTM in vitro scRNA-seq data to study global changes in gene expression in comparison to cells in tissue in situ. We have performed extensive preprocessing and quality control, allowing the research community to access and utilize this public resource.

Discovery of BGB-8035, a Highly Selective Covalent Inhibitor of Bruton's Tyrosine Kinase for B-Cell Malignancies and Autoimmune Diseases.

Bruton's tyrosine kinase (BTK) plays an essential role in B-cell receptor (BCR)-mediated signaling as well as the downstream signaling pathway for Fc receptors (FcRs). Targeting BTK for B-cell malignancies by interfering with BCR signaling has been clinically validated by some covalent inhibitors, but suboptimal kinase selectivity may lead to some adverse effects, which also makes the clinical development of autoimmune disease therapy more challenging. The structure-activity relationship (SAR) starting from zanubrutinib (BGB-3111) leads to a series of highly selective BTK inhibitors, in which BGB-8035 is located in the ATP binding pocket and has similar hinge binding to ATP but exhibits high selectivity over other kinases (EGFR, Tec, etc.). With an excellent pharmacokinetic profile as well as demonstrated efficacy studies in oncology and autoimmune disease models, BGB-8035 has been declared a preclinical candidate. However, BGB-8035 showed an inferior toxicity profile compared to that of BGB-3111.