Synthesis and biological evaluation of optically active Z250-1659 as a synthetic lethal agent against BAP1-deficient...

Synthetic lethality has emerged as an attractive therapeutic strategy for cancers harboring tumor suppressor gene alterations, as exemplified by the clinical success of PARP inhibitors in BRCA1/2-deficient cancers. We identified (±)-Z250-1659 as a synthetic lethal compound against BAP1-deficient mesothelioma cells through screening of a chemical library. To determine the active enantiomer, both enantiomers of Z250-1659 were prepared by organic synthesis and biologically evaluated, revealing that (S)-Z250-1659 is primarily responsible for the synthetic lethal activity. Notably, (±)-Z250-1659 exhibited activity nearly comparable to that of synthesized (S)-Z250-1659, despite the limited activity of the (R)-Z250-1659.