Fragment-Based Discovery of MRTX1719, a Synthetic Lethal Inhibitor of the PRMT5•MTA Complex for the Treatment of -Deleted Cancers.

The PRMT5•MTA complex has recently emerged as a new synthetically lethal drug target for the treatment of -deleted cancers. Here, we report the discovery of development candidate . is a potent and selective binder to the PRMT5•MTA complex and selectively inhibits PRMT5 activity in -deleted cells compared to -wild-type cells.

Highly Efficient, Convergent, and Enantioselective Synthesis of Phthioceranic Acid.

A new strategy for highly concise, convergent, and enantioselective access to polydeoxypropionates has been developed. ZACA-Pd-catalyzed vinylation was used to prepare smaller deoxypropionate fragments, and then two key sequential Cu-catalyzed stereocontrolled sp(3)-sp(3) cross-coupling reactions allowed convergent assembly of smaller building blocks to build-up long polydeoxypropionate chains with excellent stereoselectivity. We employed this strategy for the synthesis of phthioceranic acid, a key constituent of the cell-wall lipid of Mycobacterium tuberculosis, in just 8 longest linear steps with full stereocontrol.