AM-6761

AM-6761 is broadly comparable to the previously reported compound AMG-232 in terms of high potency and robust effects in cells. AM-6761 would be a confirmatory molecule from the same chemical scaffold. High selectivity has been shown for MDM2 over MDMX, and for effects on cells expressing WT P53 over P53-deficient cells. Broader off-target selectivity data has not been published and would be beneficial to aid interpretation of the effects of the compound in wider cell-based screening. Pharmacokinetic and pharmacodynamics data support the use of AM-6761 in mouse models in vivo. AM-6761 shows lower efficacy (fewer tumour regressions at high dose) in xenograft tumours than AMG-232, which might, therefore, be preferred for in vivo studies.

This is a good probe for cell and mouse studies, but it is probably less useful than related Amgen compounds that have entered human testing, such as AMG232. In a mouse xenograft SJSA-1 osteosarcoma tumor model the compound caused 6% tumor reduction at the highest dose, 50 mg/kg.

This is a high quality probe derived from AMG232 and broadly comparable to that clinical agent, with similar potency and in vivo anti-tumor activity in an SJSA-1 mouse model. Publications of AMG232 and AM-6761 are highly similar in assays and format and can be compared for further details. This compound is very selective for MDM2 compared to MDMX (IC₅₀>100 uM). Due to chemical similarity to AMG232, this compound could be viewed as a confirmatory molecule with the same scaffold.