Recent advancements in the condensation of alcohols with pronucleophiles by the Mitsunobu reaction are described.

Introduction: Myeloid cell leukemia-1 (MCL-1) is an anti-apoptotic member of the B-cell lymphoma-2 (BCL-2) family of proteins that regulate apoptosis. Elevated levels of MCL-1 contributes to tumorigenesis and resistance, not only to conventional chemotherapies but also to targeted therapies, including the BCL-2 selective inhibitor venetoclax. For these reasons, researchers in both the pharmaceutical industry and academia have been actively seeking MCL-1 inhibitors in the quest for new anti-cancer drugs. Areas covered: This review covers the patent literature on the discovery and development of small-molecule inhibitors of MCL-1 since 2017. Expert opinion: Pharmacological methods to inhibit the oncogenic activity of the MCL-1 protein have certainly come of age with numerous inhibitors spanning a variety of chemotypes that inhibit MCL-1 in the picomolar range with on-target cell activity in the nanomolar range. The exquisite selectivities that have been reported appear to be largely attributed to the plasticity of the p2 sub-pocket, which was first demonstrated in 2013 by a crystal structure of an indole-2-carboxylic acid derivative bound to MCL-1. Indeed, Vanderbilt, Abbvie, AstraZeneca and The Broad Institute have all independently developed research programs around this motif, which has culminated in the macrocyclic inhibitor AZD5991 that is presently in a Phase 1 clinical trial for patients with hematological malignancies (NCT03218683). Inhibitors comprising two other very distinct chemotypes have likewise advanced to clinical trials and are also reported herein. In fact, seminal research by Servier with a thienopyrimidine scaffold demonstrated for the first time that MCL-1 inhibition is tolerable in animal models of cancer, which paved the way for clinical trials. After more than a decade of research, the hurdles and obstacles are mostly behind us, and uncovering the therapeutic impact of disrupting the protein–protein interactions of MCL-1 in humans is imminent.

Introduction: The myeloid cell leukemia−1 (MCL-1) protein is one of the key anti-apoptotic members of the B-cell lymphoma-2 (BCL-2) protein family. Over-expression of MCL-1 has been closely related to tumor progression as well as to resistance, not only to traditional chemotherapies but also to targeted therapeutics including BCL-2 inhibitors such as ABT-263. Therefore, there has been extensive research and development in the last decade in both academic and industrial settings to address this unmet medical need. Areas covered: This review covers the research and patent literature of the past 10 years in the field of discovery and development of small-molecule inhibitors of the MCL-1 anti-apoptotic protein. Expert opinion: Small-molecule strategies to disrupt the protein-protein interactions between MCL-1 and its pro-apoptotic counterparts, such as BAK and BIM, have recently emerged. Several small-molecules based on different scaffolds describe promising in vitro data as MCL-1 selective inhibitors. While many lead compounds remain at the in vitro preclinical development stage, the two most recent patent applications describe promising in vivo data, and one small molecule inhibitor has recently entered into clinical development. It is such an exciting moment that the long awaited clinical studies will generate some insight into the therapeutic potential of this anti-cancer approach, and possibly facilitate the further development of other early stage inhibitors.