Small-molecule IKKβ activation modulator (IKAM) targets MAP3K1 and inhibits pancreatic tumor growth.

Activation of inhibitor of nuclear factor NF-κB kinase subunit-β (IKKβ), characterized by phosphorylation of activation loop serine residues 177 and 181, has been implicated in the early onset of cancer. On the other hand, tissue-specific IKKβ knockout in Kras mutation-driven mouse models stalled the disease in the precancerous stage. In this study, we used cell line models, tumor growth studies, and patient samples to assess the role of IKKβ and its activation in cancer.

Design, Synthesis, and Targeted Delivery of an Immune Stimulant that Selectively Reactivates Exhausted CAR T Cells.

Although chimeric antigen receptor (CAR) T cells have demonstrated significant promise in suppressing hematopoietic cancers, their applications in treating solid tumors have been limited by onset of CAR T cell exhaustion that accompanies continuous CAR T cell exposure to tumor antigen. To address this limitation, we have exploited the abilities of recently designed universal CARs to bind fluorescein and internalize a fluorescein-TLR7 agonist conjugate by CAR-mediated endocytosis. We demonstrate here that anti-fluorescein CAR-mediated uptake of a fluorescein-TLR7-3 conjugate can reactivate exhausted CAR T cells, leading to dramatic reduction in T cell exhaustion markers (PD-1 Tim-3 ) and shrinkage of otherwise resistant tumors without inducing systemic activation of the immune system.

Sensitive manipulation of CAR T cell activity using a chimeric endocytosing receptor.

Background: Most adoptive cell therapies (ACTs) suffer from an inability to control the therapeutic cell's behavior following its transplantation into a patient. Thus, efforts to inhibit, activate, differentiate or terminate an ACT after patient reinfusion can be futile, because the required drug adversely affects other cells in the patient.

Methods: We describe here a two domain fusion receptor composed of a ligand-binding domain linked to a recycling domain that allows constitutive internalization and trafficking of the fusion receptor back to the cell surface.

FtsZ inhibition and redox modulation with one chemical scaffold: Potential use of dihydroquinolines against mycobacteria.

The dual effect of FtsZ inhibition and oxidative stress by a group of 1,2-dihydroquinolines that culminate in bactericidal effect on mycobacterium strains is demonstrated. They inhibited the non-pathogenic Mycobacterium smegmatis mc(2) 155 with MIC as low as 0.9 μg/mL and induced filamentation.

Cyclin Dependent Kinase 9 Inhibitors for Cancer Therapy.

Cyclin dependent kinase (CDK) inhibitors have been the topic of intense research for nearly 2 decades due to their widely varied and critical functions within the cell. Recently CDK9 has emerged as a druggable target for the development of cancer therapeutics. CDK9 plays a crucial role in transcription regulation; specifically, CDK9 mediated transcriptional regulation of short-lived antiapoptotic proteins is critical for the survival of transformed cells.

N-Methylpyrrolidone Hydroperoxide/Cs2 CO3 as an Excellent Reagent System for the Hydroxy-Directed Diastereoselective Epoxidation of Electron-Deficient Olefins.

This report introduces N-methylpyrrolidone hydroperoxide (NMPOOH)/base as an excellent reagent system for hydroxy-directed syn selective epoxidation of electron-deficient olefins, characterized by high diastereoselectivity, short reaction times and remarkable chemoselectivity, especially in presence of oxidatively labile nitrogen or sulfur atoms. NMPOOH also proves efficient in the oxidation of electron-deficient aromatic aldehydes, in the removal of oxazolidinone chiral auxiliary, and in the functionalization of alkenes and alkynes, showing wide application potential.

Multi-chelation approach towards natural product-like skeletons: one-pot access to a nitrogen-containing tetracyclic framework from AlaAla dipeptide.

Reductive transformation of the dipeptide BocAlaAlaOMe to a complex, internally charge-stabilized, natural product-like skeleton in one synthetic step is discussed. Stepwise replacement of the B-H bonds in borane by B-N or B-O resulted in incorporation of three boron atoms in a tetracyclic framework whereby one is stereogenic!