title: Oral proteasome inhibitor with strong preclinical efficacy in myeloma models.
abstract: BACKGROUND
  The proteasome is a validated anti-cancer target and various small-molecule inhibitors are currently in clinical development or on the market. However, adverse events and resistance associated with those proteasome inhibitors indicate the need for a new generation of drugs. Therefore, we focused on developing an oral proteasome inhibitor with improved efficacy and safety profiles.
  
  
  METHODS
  The in vitro inhibition of the 20S proteasome catalytic activities was determined in human multiple myeloma (MM) cellular lysates with fluorogenic peptide substrates specific for each catalytic subunit. Cell cytotoxicity was assessed with the ATP bioluminescence assay using human cell samples from tumor cell lines, MM patients or normal healthy donors. In mice bearing human MM xenografts, a single dose of LC53-0110 was administered orally, and concentration-time profiles of LC53-0110 and the 20S proteasome catalytic activities in plasma, blood, and tumor were determined. The efficacy of repeat-dose compound with regard to tumor growth inhibition in vivo was also evaluated in the same MM xenograft models.
  
  
  RESULTS
  LC53-0110 is far more specific for the chymotrypsin-like proteolytic (β5) site of the 20S proteasome as compared to bortezomib, carfilzomib, or ixazomib. LC53-0110 treatment showed accumulation of ubiquitinated proteins, inhibited cell viability with a low nM range potency in various tumor cell lines, and showed potent activity on CD138(+) cells isolated from MM patients who are resistant/refractory to current FDA-approved drug treatment. When a single dose was administered orally to tumor-bearing mice, LC53-0110 showed both greater maximum and sustained tumor proteasome inhibition as compared with ixazomib in MM xenograft models. The robust pharmacodynamic responses in tumor correlated with tumor growth regression. In addition, LC53-0151, an analog of LC53-0110, in combination with pomalidomide, a third-generation immunomodulatory drug, showed synergistic inhibition of tumor growth both in vitro and in the xenograft mouse model.
  
  
  CONCLUSIONS
  In view of the in vitro, in vivo, and ex vivo profiles, further investigation of additional LC compounds in preclinical studies is warranted for the nomination of a clinical development candidate.
authors.affiliation: R&D Center, LG Life Sciences, Ltd, Daejeon, South Korea.
authors.forename: Jonghoon
authors.initials: J
authors.lastname: Park
authors.affiliation: R&D Center, LG Life Sciences, Ltd, Daejeon, South Korea.
authors.forename: Eok
authors.initials: E
authors.lastname: Park
authors.affiliation: R&D Center, LG Life Sciences, Ltd, Daejeon, South Korea.
authors.forename: Cheol-Kyu
authors.initials: CK
authors.lastname: Jung
authors.affiliation: R&D Center, LG Life Sciences, Ltd, Daejeon, South Korea.
authors.forename: Seung-Wan
authors.initials: SW
authors.lastname: Kang
authors.affiliation: R&D Center, LG Life Sciences, Ltd, Daejeon, South Korea.
authors.forename: Byung Gyu
authors.initials: BG
authors.lastname: Kim
authors.affiliation: R&D Center, LG Life Sciences, Ltd, Daejeon, South Korea.
authors.forename: Youngjoo
authors.initials: Y
authors.lastname: Jung
authors.affiliation: R&D Center, LG Life Sciences, Ltd, Daejeon, South Korea.
authors.forename: Tae Hun
authors.initials: TH
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Lim
authors.affiliation: Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Sung-Eun
authors.initials: SE
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Chang-Ki
authors.initials: CK
authors.lastname: Min
authors.affiliation: R&D Center, LG Life Sciences, Ltd, Daejeon, South Korea. wonk12pharm@yahoo.com.
authors.forename: Kwang-Ai
authors.initials: KA
authors.lastname: Won
mesh_terms: D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D001896:Boron Compounds / Q000008:administration & dosage; D000069286:Bortezomib / Q000008:administration & dosage; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D004357:Drug Synergism; D005260:Female; D005998:Glycine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D009842:Oligopeptides / Q000008:administration & dosage; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D061988:Proteasome Inhibitors / Q000008:administration & dosage*; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001896:Boron Compounds; D009842:Oligopeptides; D061988:Proteasome Inhibitors; D013792:Thalidomide; D000069286:Bortezomib; C548400:ixazomib; C524865:carfilzomib; C467566:pomalidomide; D046988:Proteasome Endopeptidase Complex; D005998:Glycine
keywords: Combination therapy; Multiple myeloma; Oral drug; Pomalidomide; Proteasome inhibitor