Aim: With the decreasing costs of genomics technologies, ever more data is being put into the public domain. Scientific papers only highlight a fraction of the information in the data, consequently further mining can answer drug discovery relevant questions and identify new targets. In this work we developed a bioinformatics pipeline, based on the collateral vulnerability hypothesis, to integrate several sources of public data and identify novel targets to form the basis of a new drug discovery project. Methods: Genomic data from TCGA was integrated with phenotypic data extracted from Mousemine, Flymine and Wormbase to identify loss-of-function aberrations in genes from families with essential predicted function. Follow-up experiments investigated the effect of siRNA knockdown of paralogs of genes of interest on various cellular phenotypes including proliferation, survival and senescence in gene deficient cell lines. A fragment screen was used to assess drugability of genes of interest. Results: The pipeline has been applied to several cancer types, and as a result a drug discovery project has been initiated against SMARCA2 in SMARCA4-deficient lung adenocarcinoma. SMARCA4 is a bromodomain-containing transcriptional co-activator within the multi-subunit SWF/SNF complex, which also possesses helicase and ATPase activities and functions to alter chromatin structure. SMARCA4-deficient cell lines harbour abrogating mutations, and previous studies have demonstrated that knockdown of SMARCA2, its functional paralog, in SMARCA4-deficient cell lines results in reduced cellular proliferation and survival. Moreover, SMARCA2 has been shown to be inactivated by epigenetic silencing in a proportion of human tumours. The collateral vulnerability hypothesis was tested in a panel of lung adenocarcinoma cell lines with SMARCA2- and/or SMARCA4-deficiencies. Experiments investigating the effect of siRNA knockdown confirmed both our hypothesis and the published data. A fragment screen against the bromodomain of SMARCA2 generated a high ‘ligandability’ index, suggesting that this target is druggable. Conclusion: SMARCA2 has been validated by our work and others as a target in SMARCA4 deficient lung adenocarcinoma. Future work will focus on elucidating the role of the bromodomain and the ATPase domain in SMARCA2/4 activity, and we are actively pursuing the identification of small molecule inhibitors of SMARCA2. An HTS has been undertaken against a library of >700 million compounds in a DNA-encoded library to identify novel hit matter that may ultimately be developed for therapeutic value. Citation Format: Phil Chapman, Nikki March, Graeme Thomson, Emma Fairweather, Samantha Fritzl, James Hitchin, Nicola Hamilton, Allan Jordan, Ian Waddell, Donald Ogilvie. Inhibition of SMARCA2: a novel target for SMARCA4-deficient lung adenocarcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5429. doi:10.1158/1538-7445.AM2015-5429
RET (REarranged during Transfection) is a receptor tyrosine kinase (TK), which plays pivotal roles in regulating cell survival, differentiation, proliferation, migration and chemotaxis. Activating mutations in RET (C634W and M918T) have been identified in both familial and sporadic forms of medullary thyroid carcinoma (MTC) and correlate with aggressive disease progression, validating RET as a classical oncogene. Furthermore the recent identification of RET fusions (CCDC6-RET and KIF5B-RET) present in ∼1% of lung adenocarcinoma (LAD) patients has renewed interest in the identification and development of more selective RET inhibitors lacking the toxicities associated with the current treatments. At present, there are no known specific RET inhibitors in clinical development, although many potent inhibitors of RET have been identified opportunistically through selectivity profiling of compounds initially designed to target other TKs. Such “secondary RET inhibitors” include the clinical agents Vandetanib and Cabozantinib, both approved for use in MTC, but additional pharmacological activities (most notably inhibition of KDR) lead to dose-limiting toxicity. Using a robust screening cascade developed in house, we have measured RET and KDR inhibitory activity in vitro and in relevant cell line models to assess compound potency and selectivity. Anti-proliferative activity and off-target toxicity of these agents have also been measured. Although these competitor compounds displayed reasonable RET potency in cellular assays and this translated into anti-proliferative effects in our MTC and LAD disease models, as expected none met our target candidate criteria, clearly highlighting the need for therapeutic agents with improved selectivity. Guided by structure-based drug design, we have identified and optimised a novel series of potent and selective inhibitors of the RET kinase domain. These agents met our stringent criteria for enzyme and cell selectivity and, whilst potent in a RET-driven cell line, display little overt toxicity in a matched non-RET driven cell line. Herein, we describe the chemical optimisation of these agents and, using structural information, rationalise their improved selectivity. Citation Format: Roger J. Butlin, Rebecca Newton, Mandy Watson, Gemma Hopkins, Ben Acton, Kate Bowler, Samantha Fritzl, Kristin Goldberg, Niall Hamilton, Sarah Holt, Stuart Jones, Allan Jordan, Nikki March, Daniel Mould, Helen Small, Alexandra Stowell, Ian Waddell, Bohdan Waszkowycz, Donald Ogilvie. The identification and structure-guided optimisation of potent and selective inhibitors of oncogenes in medullary thyroid carcinoma and lung adenocarcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 778. doi:10.1158/1538-7445.AM2015-778
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