BRD9500 is an orally active inhibitor of phosphodiesterases 3 (PDE3) with IC 50 s of 10 and 27 nM for PDE3A and PDE3B, respectively. BRD9500 is active in an SK-MEL-3 xenograft model of cancer [1].

PDE3A:10 nM, PDE3B:27 nM

As an analog of DNMDP, BRD9500 effectively and selectively targets PDE3A and PDE3B, disrupting cancer cell viability by facilitating the interaction between PDE3A/B and SLFN12. This compound has demonstrated potent activity against the SK-MEL-3 melanoma cell line, with an EC50 of 1 nM, and against HeLa cells, with an EC50 of 1.6 nM. Furthermore, at a concentration of 10 μM over 8 hours, BRD9500 stabilizes the PDE3A-SLFN12 interaction in HeLa cells, evidenced by a Western Blot Analysis. This analysis revealed clear detection of the SLFN12-V5 fusion protein via coimmunoprecipitation and immunoblotting with an anti-V5 antibody, confirming the compound's targeted mechanism of action.

BRD9500, administered orally at dosages of 10, 20, and 50 mg/kg, effectively inhibits the growth of SK-MEL-3 melanoma in mouse models, demonstrating potent antitumor activity, particularly at 50 mg/kg. Notably, it exhibits high plasma concentrations when given either intravenously (iv) at 1 mg/kg or orally (po) at 2 mg/kg, persisting for over eight hours. This pharmacokinetic profile, combined with its tolerability—evidenced by the absence of significant weight loss or toxicities in treated animals—positions BRD9500 as a promising agent for in vivo xenograft experimentation. The study utilized female NMRI nude mice implanted with SK-MEL-3 melanoma cell tumor xenografts, applying oral doses of 10 and 20 mg/kg twice daily and 50 mg/kg once daily, with the highest dose yielding the most pronounced antitumor effects.