The contribution of physicochemical properties to multiple in vitro cytotoxicity endpoints

Toxicology in Vitro : an International Journal Published in Association with BIBRA
Shuyan LuYvonne Will

Abstract

Attrition due to safety reasons remains a serious problem for the pharmaceutical industry. This has prompted efforts to develop early predictive in vitro screens that can assist in selecting compounds with a more desirable safety profile early on in the drug discovery process. Here we examined the relationship between physicochemical properties, such as partition coefficient (clogP), topological polar surface area (TPSA), acid dissociation constant (pK(a)), and in vitro mechanistic endpoints generated using a high content imaging approach. We demonstrate in our initial analysis that compounds with clogP>2 and pK(a)>5.5 flagged more endpoints than compounds with clogP ≤ 2 and pK(a) ≤ 5.5. In contrast, TPSA did not stand on its own in predicting cytotoxicity. When this knowledge was applied to eight different mechanistic cytotoxicity endpoints (cell loss, apoptosis, ER stress, DNA fragmentation, mitochondrial potential, nuclear size, neutral lipids/steatosis and lysosomal mass), we found that compounds with such properties preferentially flagged in the lysosomal endpoint. We also saw a slight enrichment of such compounds in the endpoints cell loss, DNA fragmentation and nuclear size. We demonstrate that lysosomal compound accumul...Continue Reading

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Citations

Nov 28, 2013·PloS One·Roshan AshoorShuyan Lu
Jan 23, 2014·Chemical Research in Toxicology·Shana J SturlaManuel C Peitsch
Mar 17, 2015·Toxicological Sciences : an Official Journal of the Society of Toxicology·Su Khoh-ReiterShuyan Lu
Oct 23, 2012·Toxicology in Vitro : an International Journal Published in Association with BIBRA·E Koslov-DavinoT Schroeter
Jan 30, 2013·Journal of Medicinal Chemistry·Ákos Tarcsay, György M Keserű
Nov 16, 2017·Chemical Biology & Drug Design·Govindan Subramanian, Gennady Poda
Jan 22, 2020·Journal of Cellular Physiology·Nele Van Der SteenGodefridus J Peters
Mar 17, 2017·PloS One·Shuyan LuBart A Jessen
Nov 17, 2020·Frontiers in Oncology·Marco VaraldaDaniela Capello
Dec 19, 2020·ACS Medicinal Chemistry Letters·Maria ChatzopoulouAngela J Russell

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