M3258

M3258 is an orally bioavailable, potent, reversible and highly selective immunoproteasome subunit LMP7 (β5i) inhibitor. M3258 exerts high biochemical ( IC 50 =3.6 nM) and cellular ( IC 50 =3.4 nM) potency against the LMP7 subunit. M3258 shows strong antitumor efficacy in multiple myeloma xenograft models. M3258 leads to a significant and prolonged suppression of tumor LMP7 activity and ubiquitinated protein turnover and the induction of apoptosis in multiple myeloma cells In Vitro M3258 inhibits human LMP7 with a mean IC 50 of 4.1 nM. M3258 displays weak activity against the constitutive proteasome subunit β5 (mean IC 50 =2519 nM). M3258 potently inhibits LMP7 in the human multiple myeloma cell lines MM.1S and U266B1 and in human, rat, and dog PBMCs with IC 50 s between 2 and 37 nM. M3258 induces a >four fold accumulation of ubiquitinated proteins with an EC 50 of 1980 nM in MM.1S cells. M3258 interferes with immunoproteasome function. M3258 also induces apoptosis assessed by caspase 3/7 activity (EC 50 =420 nM;>3.5-fold induction) and reduces MM.1S cell viability (IC 50 =367 nM). MCE has not independently confirmed the accuracy of these methods. They are for reference only. Cell Viability AssayCell Line: MM.1S cells Concentration: 0.01-100 nM Incubation Time: 2 hours Result: Potently inhibited LMP7 in the human multiple myeloma cell lines MM.1S (IC 50 =2.2 nM). In Vivo M3258 (1 mg/kg; 10 mg/kg) shows superior antitumor efficacy in selected multiple myeloma and mantle cell lymphoma xenograft models compared with the approved nonselective proteasome inhibitors bortezomib and ixazomib. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Animal Model: Female H2d Rag2 mice or female CB-17 SCID mice (U266B1 subcutaneous xenograft model; MM.1S subcutaneous xenograft model)Dosage: 1 mg/kg in U266B1 subcutaneous xenograft model; 10 mg/kg in MM.1S subcutaneous xenograft model Administration: P.o.; either once daily, every 2 days or twice weekly (days 1 and 4) Result: Displayed significant and strong antitumor efficacy. IC50& Target:LMP7

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