Related Experiment Video
Updated: Mar 23, 2026
Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
Published on: May 15, 2019
Oral proteasome inhibitor with strong preclinical efficacy in myeloma models
Jonghoon Park1, Eok Park1, Cheol-Kyu Jung1
1R&D Center, LG Life Sciences, Ltd, Daejeon, South Korea.
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.
Method:
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.
Insights
A novel oral proteasome inhibitor, LC53-0110, demonstrates high specificity and potent anti-cancer activity against multiple myeloma (MM) cells, including drug-resistant types. Further preclinical studies are recommended for clinical development.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- The proteasome is a key anti-cancer target, but existing inhibitors cause adverse events and resistance.
- There is a critical need for novel proteasome inhibitors with improved efficacy and safety profiles.
- Development of an oral proteasome inhibitor offers potential for improved patient compliance and treatment outcomes.
Purpose of the Study:
- To develop and characterize a new generation of oral proteasome inhibitors.
- To evaluate the preclinical efficacy and safety of LC53-0110 and its analogs.
- To identify a potential clinical development candidate for treating proteasome-related cancers.
Main Methods:
- In vitro assessment of 20S proteasome inhibition in human multiple myeloma (MM) lysates.
- Cell cytotoxicity assays using tumor cell lines and patient-derived MM cells.
- In vivo studies in MM xenograft mouse models to determine pharmacokinetics, pharmacodynamics, and efficacy.
Main Results:
- LC53-0110 exhibits superior specificity for the chymotrypsin-like (β5) site compared to existing drugs.
- LC53-0110 effectively inhibits cell viability and induces protein ubiquitination in MM cells, including resistant populations.
- In vivo, LC53-0110 demonstrated superior tumor proteasome inhibition and tumor growth regression compared to ixazomib.
Conclusions:
- LC53-0110 displays promising preclinical anti-cancer activity and a favorable specificity profile.
- Combination therapy with analogs like LC53-0151 and pomalidomide shows synergistic effects.
- Further preclinical investigation of LC compounds is warranted for clinical candidate nomination.
