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Disparate anticancer activity of structurally similar multi-kinase inhibitors through cumulative differential effects on individual targets

ABSTRACT: Disparate anticancer activity of structurally similar multi-kinase inhibitors through cumulative differential effects on individual targets

PROVIDER: PRJNA523517 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8601611_1.fastq.gz	Fastqsanger.gz
	SRR8601611_2.fastq.gz	Fastqsanger.gz
	SRR8601612_1.fastq.gz	Fastqsanger.gz
	SRR8601612_2.fastq.gz	Fastqsanger.gz
	SRR8601613_1.fastq.gz	Fastqsanger.gz

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Disparate anticancer activity of structurally similar multi-kinase inhibitors through cumulative differential effects on individual targets

Project description:Despite recent improvements many cancer patients do not respond to immune or targeted drugs and require new therapies. Through a systems pharmacology approach including phenotypic screening, chemical and phosphoproteomics and RNA-Seq, we elucidated the mechanism of action underlying the differential anticancer activity of two structurally related multi-kinase inhibitors, foretinib and cabozantinib, in lung cancer cells. Biochemical and cellular target validation using probe molecules and RNA interference revealed a polypharmacology mechanism of foretinib involving MEK1/2, FER and AURKB, which were each more potently inhibited by foretinib than cabozantinib. Based on this, we rationally developed a synergistic combination of foretinib with barasertib, a more potent AURKB inhibitor, for MYC-amplified small cell lung cancer. This systems pharmacology approach showed that small structural changes of drugs can cumulatively through multiple targets result in pronounced anticancer activity differences and that detailed mechanistic understanding can lead to new repurposing opportunities for cancers with unmet medical need.

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Divergent polypharmacology-driven cellular activity of structurally similar multi-kinase inhibitors through cumulative differential effects on individual targets: Drug Pulldowns

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Project description:Comparing biological similarity with in vitro test is expected to improve the reliability of read-across for systemic toxicity without animal test. However, because of few case studies, it was hindered to use of this concept for regulatory context. Thus, we compared biological similarity with in vitro test for structurally similar chemicals to demonstrate its validity for grouping chemicals and extract key considerations in read-across. In this study, we selected the hepatotoxicity of Naphthalene and its structurally similar analogs which have 90-day repeated dose toxicity data including 2,7-Naphthalenediol, 1,5-Naphthalenediol, and 1-Naphthol. To elucidate the potential mechanisms and compared them, we conducted in vitro microarray analysis with rat primary hepatocytes

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The validation case study of read-across based on IATA for hepatotoxicity of Naphthalene and its structurally similar analogs

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