The direct, by-product–free conversion of basic feedstocks to products of medicinal and agricultural relevance is a broad goal of chemical research. Butadiene is a product of petroleum cracking and is produced on an enormous scale (about 12 × 106 metric tons annually). Here, with the use of a ruthenium catalyst modified by a chiral phosphate counterion, we report the direct redox-triggered carbon-carbon coupling of alcohols and butadiene to form products of carbonyl crotylation with high levels of anti-diastereoselectivity and enantioselectivity in the absence of stoichiometric by-products.

The transcriptional enhanced associate domain (TEAD) family of transcription factors serves as the receptors for the downstream effectors of the Hippo pathway, YAP and TAZ, to upregulate the expression of multiple genes involved in cellular proliferation and survival. Recent work identified TEAD S-palmitoylation as critical for protein stability and activity as the lipid tail extends into a hydrophobic core of the protein. Here, we report the identification and characterization of a potent small molecule that binds the TEAD lipid pocket (LP) and disrupts TEAD S-palmitoylation. Using a variety of biochemical, structural, and cellular methods, we uncover that TEAD S-palmitoylation functions as a TEAD homeostatic protein level checkpoint and that dysregulation of this lipidation affects TEAD transcriptional activity in a dominant-negative manner. Furthermore, we demonstrate that targeting the TEAD LP is a promising therapeutic strategy for modulating the Hippo pathway, showing tumor stasis in a mouse xenograft model.

The direct α-amination of ketones, esters, and aldehydes has been accomplished via copper catalysis. In the presence of catalytic copper(II) bromide, a diverse range of carbonyl and amine substrates undergo fragment coupling to produce synthetically useful α-amino substituted motifs. The transformation is proposed to proceed via a catalytically generated α-bromo carbonyl species; nucleophilic displacement of the bromide by the amine then delivers the α-amino carbonyl adduct while the catalyst is reconstituted. The practical value of this transformation is highlighted through one-step syntheses of two high–profile pharmaceutical agents, Plavix and amfepramone.

Breast cancer remains a leading cause of cancer death in women, representing a significant unmet medical need. Here, we disclose our discovery efforts culminating in a clinical candidate, 35 (GDC-9545 or giredestrant). 35 is an efficient and potent selective estrogen receptor degrader (SERD) and a full antagonist, which translates into better antiproliferation activity than known SERDs (1, 6, 7, and 9) across multiple cell lines. Fine-tuning the physiochemical properties enabled once daily oral dosing of 35 in preclinical species and humans. 35 exhibits low drug−drug interaction liability and demonstrates excellent in vitro and in vivo safety profiles. At low doses, 35 induces tumor regressions either as a single agent or in combination with a CDK4/6 inhibitor in an ESR1 Y537S mutant PDX or a wild-type ERα tumor model. Currently, 35 is being evaluated in Phase III clinical trials.

The transcription factor RORγ plays a critical role in the expression of pro-inflammatory cytokine interleukin IL-17 and is therefore an attractive target for the treatment of inflammatory diseases. Interest in this molecular target has been heightened by the advancement of orally and topically administered RORγ modulators into clinical trials. Areas covered: The present review seeks to summarize published patent applications from assignee companies that have disclosed Investigational New Drug (IND) filings for small molecule RORγ/RORγt antagonists and inverse agonists. Expert opinion: The field of RORγ research is extremely competitive, with the majority of companies targeting psoriasis as the primary disease indication. Vitae Pharmaceuticals is currently the most advanced, with a potential first-in-class oral RORγ-modulator for the treatment of psoriasis. Future efforts will likely expand into potential applications of RORγ-modulators in the lesser explored immune-related areas of rheumatoid arthritis, type 1 diabetes, lupus, and irritable bowel disorder, as well as cancer immunotherapy and castration-resistant prostate cancer.