Identification of a Novel and Efficacious Oral Proteasome Inhibitor As a Potential Clinical Development Candidate

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 call for a new generation of drugs.

LC53-0110 and its analogues were identified as novel, reversible, selective, potent, and orally bioavailable proteasome inhibitors which have physicochemical profiles that are distinct from bortezomib, carfilzomib or ixazomib. As compared to those inhibitors, LC53-0110 is far more selective for the chymotrypsin-like proteolytic (β5) site of the 20S proteasome, with an IC50 value of less than 10 nM over the trypsin-like site and the caspase-like site. LC53-0110 treatment showed accumulation of ubiquitinated proteins and inhibited cell viability with a low nM range potency in various hematologic and solid tumor cell lines including multiple myeloma (MM), lymphoma, colon tumor, breast tumor, and lung tumor.

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 and solid tumor xenograft models. The robust pharmacodynamic responses in tumor translated to the efficacy studies. In the RPMI8226 (MM) efficacy model, oral administration twice a week at 50 mg/kg inhibited tumor growth 68% by three weeks. In the MM.1S (MM) efficacy model, oral administration twice a week at 100 mg/kg completely abolished measurable tumor mass by one week and prevented any tumor re-growth during the three-week study period.

In the initial studies, LC53-0110 also showed potent activity on freshly isolated CD138+ cells from MM patients (pts) who are resistant/refractory (r/r) to current FDA-approved drug treatment. Further studies, including comparison of the naïve pts vs. thalidomide r/r pts and bortezomib r/r pts as well as their potential clinical implications will be discussed.