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. 2024 Apr 10;38(6):1223–1235. doi: 10.1038/s41375-024-02241-7

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© The Author(s) 2024

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 2 — A Heat map depicting drug concentrations resulting in 50% cell death (IC₅₀) of 32 combination candidates determined using a 5-point log₁₀-fold dilution range in a panel of 6 PDX leukemic samples. Each column represents an individual leukemia PDX sample, and each row represents a unique drug. Mean cell viability was determined in technical triplicate after 96 h drug exposure using fluorescence image-based microscopy (N = 1). Absolute live cell counts were normalized to respective vehicle (DMSO) controls. Drugs chosen for further investigation are indicated by a red asterisk (). B Box plot showing the distribution of mean IC₅₀ values across each sample (N = 1). Mean MSC IC₅₀ is indicated as a grey ring (N > 3) or bound to the highest concentration if > 1 μM. Boxes represent 25th to 75th percentiles, with median as a solid line, mean as a ‘+’, and whiskers extending to the range. C Box plot showing the mean IC₅₀ for each PDX sample exposed to each library drug in combination with their respective idasanutlin doses resulting in approximately 40% cell death (IC₄₀). Data were normalized to idasanutlin-treated cells to specifically examine the additive effects of the library drugs. D Distribution of maximum attained excess over Bliss synergy scores (S_max) for each drug in combination with respective idasanutlin IC₄₀ and IC₆₀ concentrations. E Dot plot showing the median IC₅₀ of all PDX as a fraction of the clinically-reported C_max for the respective drugs versus the median S_max score of all PDX samples. Clinically-reported pharmacokinetics and sources are provided in Supplementary Table S7. The red-shaded region indicates drugs with a median IC₅₀ greater than clinically-reported limits. Results for mechlorethamine and mevastatin were omitted as clinical pharmacokinetic properties are unavailable. F Most promising drug combination candidates selected for further investigation.

Inline graphic — A Heat map depicting drug concentrations resulting in 50% cell death (IC₅₀) of 32 combination candidates determined using a 5-point log₁₀-fold dilution range in a panel of 6 PDX leukemic samples. Each column represents an individual leukemia PDX sample, and each row represents a unique drug. Mean cell viability was determined in technical triplicate after 96 h drug exposure using fluorescence image-based microscopy (N = 1). Absolute live cell counts were normalized to respective vehicle (DMSO) controls. Drugs chosen for further investigation are indicated by a red asterisk (). B Box plot showing the distribution of mean IC₅₀ values across each sample (N = 1). Mean MSC IC₅₀ is indicated as a grey ring (N > 3) or bound to the highest concentration if > 1 μM. Boxes represent 25th to 75th percentiles, with median as a solid line, mean as a ‘+’, and whiskers extending to the range. C Box plot showing the mean IC₅₀ for each PDX sample exposed to each library drug in combination with their respective idasanutlin doses resulting in approximately 40% cell death (IC₄₀). Data were normalized to idasanutlin-treated cells to specifically examine the additive effects of the library drugs. D Distribution of maximum attained excess over Bliss synergy scores (S_max) for each drug in combination with respective idasanutlin IC₄₀ and IC₆₀ concentrations. E Dot plot showing the median IC₅₀ of all PDX as a fraction of the clinically-reported C_max for the respective drugs versus the median S_max score of all PDX samples. Clinically-reported pharmacokinetics and sources are provided in Supplementary Table S7. The red-shaded region indicates drugs with a median IC₅₀ greater than clinically-reported limits. Results for mechlorethamine and mevastatin were omitted as clinical pharmacokinetic properties are unavailable. F Most promising drug combination candidates selected for further investigation.