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. Author manuscript; available in PMC: 2018 Feb 1.

Published in final edited form as: Invest New Drugs. 2016 Oct 25;35(1):11–25. doi: 10.1007/s10637-016-0398-8

Pevonedistat binds to its intended target and demonstrates expected pharmacodynamic (PD) effects in melanoma PDTX models. Sensitive and resistant PDTX were administered a single dose of pevonedistat, and tumor specimens were harvested at various time points from 30 min to 24 hrs. (a) Tumor sections were analyzed by immunohistochemistry (IHC) for NEDD8-pevonedistat adduct and CDT1, a protein substrate of cullin-RING ligases (CRLs). Representative results from a sensitive xenograft (MB1374) are shown. NEDD8-pevonedistat adduct increased rapidly at 30 min, followed by CDT1 accumulation up to 2 hrs after pevonedistat administration due to inhibition of CRL activity. (b) Levels of NEDD8-pevonedistat adduct, CDT1 and cleaved caspase 3 were quantified by the percent area of positive IHC staining at serial time points up to 72 hrs. At least 3 tumors were analyzed per time point (mean and standard deviation shown). Results from a sensitive (MB347) and a resistant (MB947) PDTX are shown.

Pevonedistat binds to its intended target and demonstrates expected pharmacodynamic (PD) effects in melanoma PDTX models. Sensitive and resistant PDTX were administered a single dose of pevonedistat, and tumor specimens were harvested at various time points from 30 min to 24 hrs. (a) Tumor sections were analyzed by immunohistochemistry (IHC) for NEDD8-pevonedistat adduct and CDT1, a protein substrate of cullin-RING ligases (CRLs). Representative results from a sensitive xenograft (MB1374) are shown. NEDD8-pevonedistat adduct increased rapidly at 30 min, followed by CDT1 accumulation up to 2 hrs after pevonedistat administration due to inhibition of CRL activity. (b) Levels of NEDD8-pevonedistat adduct, CDT1 and cleaved caspase 3 were quantified by the percent area of positive IHC staining at serial time points up to 72 hrs. At least 3 tumors were analyzed per time point (mean and standard deviation shown). Results from a sensitive (MB347) and a resistant (MB947) PDTX are shown.