The serine/threonine phosphatase family is important
in tumor progression
and survival. Due to the high conserved catalytic domain, designing
selective inhibitors is challenging. Herein, we obtained compound 28a with 38-fold enhanced PP5 selectivity (PP2A/5 IC50 = 33.8/0.9 μM) and improved drug-like properties (favorable
stability and safety, F = 82.0%) by rational drug
design based on a phase II PP2A/5 dual target inhibitor LB-100. Importantly, we found the spatial conformational restriction of
the 28a indole fragment was responsible for the selectivity
of PP5. Thus, 28a activated p53 and downregulated cyclin
D1 and MGMT, which showed potency in cell cycle arrest and reverse
temozolomide (TMZ) resistance in the U87 MG cell line. Furthermore,
oral administration of 28a and TMZ was well tolerated
to effectively inhibit tumor growth (TGI = 87.7%) in the xenograft
model. Collectively, these results implicate 28a could
be a drug candidate by reversing TMZ resistance with a selective PP5
inhibition manner.