Combination of polymeric micelle formulation of TGFβ receptor inhibitors and paclitaxel produces consistent response across different mouse models of Triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is notoriously difficult to treat due to the lack of targetable receptors and sometimes poor response to chemotherapy. The transforming growth factor beta (TGFβ) family of proteins and their receptors (TGFRs) are highly expressed in TNBC and implicated in chemotherapy-induced cancer stemness. Here, we evaluated combination treatments using experimental TGFR inhibitors (TGFβi), SB525334 (SB), and LY2109761 (LY) with paclitaxel (PTX) chemotherapy.

Development of a selective and scalable 1-indazole alkylation.

1-Alkyl indazoles are a ubiquitous and privileged motif within medicinal chemistry, yet methods to selectively furnish 1-alkyl indazoles with simple alkyl side chains remain sparse. Herein, negative data from high-throughput experimentation (HTE) enabled a confident pivot of resource from continued optimisation to the development of an alternative reaction. This workflow culminated in a methodology for the synthesis of 1-alkyl indazoles.

On the Use of Triarylsilanols as Catalysts for Direct Amidation of Carboxylic Acids.

Triarylsilanols have been reported as the first silicon-centered molecular catalysts for direct amidation of carboxylic acids with amines as identified after a screen of silanols, silanediols, disiloxanediols, and incompletely condensed silsesquioxanes as potential homogeneous catalysts. Subsequent synthesis and testing of various electronically differentiated triarylsilanols have identified tris(-haloaryl)silanols as more active than the parent triarylsilanol, where the bromide congener is found to be the most active. Catalyst decomposition can be observed by NMR methods, but RPKA methods reveal that product inhibition is operative, where tertiary amides are more inhibitory than secondary amides.

Combination of Polymeric Micelle Formulation of TGFβ Receptor Inhibitors and Paclitaxel Produce Consistent Response Across Different Mouse Models of TNBC.

Triple-negative breast cancer (TNBC) is notoriously difficult to treat due to the lack of targetable receptors and sometimes poor response to chemotherapy. The transforming growth factor-beta (TGFβ) family of proteins and their receptors (TGFR) are highly expressed in TNBC and implicated in chemotherapy-induced cancer stemness. Here we evaluated combination treatments using experimental TGFR inhibitors (TGFβi), SB525334 (SB), and LY2109761 (LY) with Paclitaxel (PTX) chemotherapy.

Intravenous heterologous prime-boost vaccination activates innate and adaptive immunity to promote tumor regression.

Therapeutic neoantigen cancer vaccines have limited clinical efficacy to date. Here, we identify a heterologous prime-boost vaccination strategy using a self-assembling peptide nanoparticle TLR-7/8 agonist (SNP) vaccine prime and a chimp adenovirus (ChAdOx1) vaccine boost that elicits potent CD8 T cells and tumor regression. ChAdOx1 administered intravenously (i.