Impact of the clinically approved BTK inhibitors on the conformation of full-length BTK and analysis of the development of BTK resistance mutations in chronic lymphocytic leukemia.

Inhibition of Bruton's tyrosine kinase (BTK) has proven to be highly effective in the treatment of B-cell malignancies such as chronic lymphocytic leukemia (CLL), autoimmune disorders, and multiple sclerosis. Since the approval of the first BTK inhibitor (BTKi), Ibrutinib, several other inhibitors including Acalabrutinib, Zanubrutinib, Tirabrutinib, and Pirtobrutinib have been clinically approved. All are covalent active site inhibitors, with the exception of the reversible active site inhibitor Pirtobrutinib.

A flexible and scalable synthesis of 4'-thionucleosides.

4'-Thionucleosides (thNAs) are synthetic nucleoside analogues that have attracted attention as leads for drug discovery in oncology and virology. Here we report a thNA synthesis that relies on a scalable α-fluorination and aldol reaction of α-heteroaryl acetaldehydes followed by a streamlined process involving carbonyl reduction, mesylate formation and a double displacement reaction using NaSH. We demonstrate the multigram preparation of 4'-thio-5-methyluridine and highlight the production of purine and pyrimidine thNAs as well as C2'-modified thNAs.

Synthesis of the Phormidolide A Macrocycle Supports the Proposed Configurational Reassignment.

We describe the successful synthesis of the phormidolide A macrocycle as a crucial step toward its total synthesis and configurational assignment. Exhaustive exploration of macrocyclization strategies revealed the detrimental effects of a bulky protecting group on the C17 hydroxyl function, leading to the successful use of a C17 -methoxybenzyloxymethyl (PMBM) ether in the macrolactonization reaction. Further elaboration of the macrocycle with a truncated C18-C23 side chain afforded an advanced C1-C23 fragment of phormidolide A.

Design, preparation and biological evaluation of new Rociletinib-inspired analogs as irreversible EGFR inhibitors to treat non-small-cell-lung cancer.

Epidermal growth factor receptor (EGFR) kinase has been implicated in the uncontrolled cell growth associated with non-small cell lung cancer (NSCLC). This has prompted the development of 3 generations of EGFR inhibitors over the last 2 decades due to the rapid development of drug resistance issues caused by clinical mutations, including T790M, L858R and the double mutant T790M & L858R. In this work we report the design, preparation and biological assessment of new irreversible 2,4-diaminopyrimidine-based inhibitors of EGFR kinase.