e20546 Background: Proteasome inhibitors, selectively inhibit the activity of proteasome in ubiquitin proteasome system, together with immunomodulatory drugs formed the basis of many treatment regimens for multiple myeloma in first-line therapy as well as for the treatment of relapsed disease. Bortezomib (Velcade), the first approved therapeutic proteasome inhibitor with a unique boronic acid as warhead, limited by its requirement for parenteral administration (intravenous or subcutaneous). The 2nd generation boronic acid – orally bioavailable Ixazomib (Ninlaro) was approved in 2015 by FDA greatly improved patient’s compliance. However, its adverse effect remained an issue in clinical application. The purpose of this study is to investigate the in vitro and in vivo antitumor activity of TQB3602, a novel orally bioavailable small molecule proteasome inhibitor, in preclinical models of multiple myeloma. Methods: The enzyme inhibition and anti-proliferative activity of TQB3602 was evaluated in 20S proteasome and MM.1S cell line. Oral administration of TQB3602 at 3 doses was used to evaluate the in vivo anti-tumor activity in MM.1S multiple myeloma xenograft (CDX) models. Results: TQB3602 displayed potent kinase inhibiting activity for 20S proteasome enzyme with IC50 15.3 nM. TQB3602 inhibited cell proliferation in MM.1S multiple myeloma cell line with IC50 10.1 nM. In the MM.1S multiple myeloma CB-17 CDX model, TQB3602 showed antitumor efficacy with TGI > 100% @7 mpk, BIW (tumor can’t be measured from day 17). Conclusions: We have identified a novel potent proteasome inhibitor TQB3602. Preclinical studies showed antitumor efficacy of TQB3602 in MM.1S multiple myeloma model. TQB3602 represents a promising clinical candidate for treating multiple myeloma and the First-in-human trial is expected in the middle of 2020.
5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (PQR309), a Potent, Brain-Penetrant, Orally Bioavailable, Pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology
