A novel small molecule inhibitor of deubiquitylating enzyme USP14 and UCHL5 induces apoptosis in multiple myeloma and overcomes bortezomib resistance

Ze Tian, Padraig D'Arcy, Xin Wang, Arghya Ray, Yu-Tzu Tai, Yiguo Hu, Ruben D. Carrasco, Paul Richardson, Stig Linder, Dharminder Chauhan and Kenneth C. Anderson

Key points

  • Deubiquitylating enzymes USP14 and UCHL5 are involved in the tumorigenesis of MM.

  • b-AP 15 is a specific USP14 and UCHL5 inhibitor, which blocks growth and induces apoptosis in MM cells.


Proteasome inhibitors have demonstrated that targeting protein degradation is effective therapy in multiple myeloma (MM). Here we show that deubiquitylating enzymes (DUBs) USP14 and UCHL5 are more highly expressed in MM cells than in normal plasma cells. USP14 and UCHL5 siRNA knockdown decrease MM cell viability. A novel 19S regulatory particle inhibitor b-AP15 selectively blocks deubiquitylating activity of USP14 and UCHL5 without inhibiting proteasome activity. b-AP15 decreases viability in MM cell lines and patient MM cells. Moreover, b-AP15 inhibits proliferation of MM cells even in the presence of bone marrow stroma cells and overcomes bortezomib-resistance. Anti-MM activity of b-AP15 is associated with growth arrest via downregulation of CDC25C, CDC2 and cyclin-B1 as well as induction of caspase-dependent apoptosis and activation of unfolded protein response. In vivo studies using distinct human MM xenograft models show that b-AP15 is well tolerated, inhibits tumor growth, and prolongs survival. Combining b-AP15 with SAHA, lenalidomide, or dexamethasone induces synergistic anti-MM activity. Our preclinical data showing efficacy of b-AP15 in MM disease models validates targeting DUBs in the ubiquitin proteasomal cascade to overcome proteasome inhibitor resistance, and provides the framework for clinical evaluation of USP14/UCHL5 inhibitors to improve patient outcome in MM.

  • Submitted May 2, 2013.
  • Accepted November 24, 2013.