A Potent Bivalent Smac Mimetic (SM-1200) Achieving Rapid, Complete, and Durable Tumor Regression in Mice

Abstract

We have designed, synthesized and evaluated a series of new compounds based upon our previously reported bivalent Smac mimetics. This led to the identification of compound 12 (SM-1200), which binds to XIAP, cIAP1 and cIAP2 with Ki values of 0.5 nM, 3.7 nM and 5.4 nM, respectively, inhibits cell growth in the MDA-MB-231 breast cancer and SK-OV-3 ovarian cancer cell lines with IC50 values of 11.0 nM and 28.2 nM, respectively. Compound 12 has a much improved pharmacokinetic profile over our previously reported bivalent Smac mimetics and is highly effective in induction of rapid and durable tumor regression in the MDA-MB-231 xenograft model. These data indicate that compound 12 is a promising Smac mimetic and warrants extensive evaluation as a potential candidate for clinical development.

Lipid-conjugated Smac analogues

“…Effects of dimerization are also apparent with dimeric analogue D3 being ~13.5× more potent than its monomeric counterpart, M6 (EC 50 (μM): 44.7±15.0 versus 3.3±0.2 respectively). previously reported results, Similarly to previously reported results 43,44 , our most active dimeric analogues contain relatively hydrophobic linker(s) with ~13–14 atoms (Cα↔C′α). Moreover, spatial geometry of linkers(s) is also an important for overall potency as compounds utilizing relatively similar linkers show diversified bioactivity ( D13-D15 ).…”

“…Surprisingly, bivalent D7 analogue showed low anticancer in vivo activity and was ~2.7× less potent than monovalent M11 (SC route). Comparison of our in vivo results with published data is somewhat difficult due to the differences in experimental conditions 35,39,44 . Nonetheless, comparing to previously reported analogue, SMAC17-2X 47 , our best lipidated compound M11 is significantly less active as reported tumor growth delay values for SMAC17-2X were: ~10.2 days at 2.5 mg/kg dose and ~23.4 days at 7.5 mg/kg dose.…”

“…Among these bivalent Smac analogues containing two AVPI mimics tethered with a linker and capable of binding to both BIR2 and BIR3 XIAP domains became the focus of investigation due to their high potency 35–37,39,43,44,47 . On the other hand, monovalent Smac mimics are also desirable due to their favorable pharmaceutical properties: low molecular weight, favorable pharmacokinetics and potential oral bioavailability 41,46 .…”

“…Generally monomeric ( M ) analogues had a sequence NMeAla-Cys/Lys-Pro-BHA which is closely related to various potent analogues developed by Wang group 35,37–39,43,44 . Based on literature data 70 , position 2, which in our analogues is occupied by either (L)Lys or (L)Cys, was chosen as viable modification/dimerization point.…”

Targeting the Inhibitor of Apoptosis Protein BIR3 Binding Domains

“…Related examples, such as SM-1258, were disclosed by researchers at the University of Michigan [83][84][85].…”