Structural and Functional Analyses of an Allosteric EYA2 Phosphatase Inhibitor That Has On-Target Effects in Human Lung Cancer Cells

Anantharajan, Jothi; Zhou, Hengbo; Zhang, Lingdi; Hotz, Taylor; Vincent, Melanie Y.; Blevins, Melanie A.; Jansson, Anna; Kuan, John Wee Liang; Ng, Elizabeth Yihui; Yeo, Yee Khoon; Baburajendran, Nithya; Lin, Grace; Hung, Alvin W.; Joy, Joma; Patnaik, Samarjit; Marugán, Juan; Rudra, Pratyaydipta; Ghosh, Debashis; Hill, Jeffrey; Keller, Thomas H.; Zhao, Rui; Ford, Heide L.; Kang, CongBao

doi:10.1158/1535-7163.mct-18-1239

Cited by 36 publications

(48 citation statements)

References 41 publications

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“…SIX4 physically interacts with the lysine demethylase UTX/KDM6A, which can be targeted by small molecule inhibitors (57). Moreover, the EYA family of transcriptional co-activators are essential for SIX1 function and harbor a druggable Tyr phosphatase activity (58,59)…”

Section: Discussionmentioning

confidence: 99%

Reciprocal regulation of pancreatic ductal adenocarcinoma growth and molecular subtype by HNF4α and SIX1/4

Camolotto

Belova

Torre-Healy

et al. 2019

Preprint

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Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a five-year survival of less than 5%. Transcriptomic analysis has identified two clinically relevant molecular subtypes of PDAC: Classical and Basal-like. The Classical subtype is characterized by a more favorable prognosis and better response to chemotherapy than the Basal-like subtype. The Classical subtype also expresses higher levels of lineage specifiers that regulate endodermal differentiation, including the nuclear receptor HNF4a. Using in vitro and in vivo PDAC models, we show that HNF4a restrains tumor growth and drives tumor cells toward an epithelial identity.Gene expression analysis from murine models and human tumors shows that HNF4a activates expression of genes associated with the Classical subtype. Although HNF4a loss is not sufficient for complete conversion to the Basal-like subtype gene expression profile, HNF4a directly represses SIX4 and SIX1, mesodermal lineage specifiers expressed in the Basal-like subtype.Finally, HNF4a-negative PDAC cells rely on expression of SIX4 and SIX1 for proliferation in vitro and in vivo. Overall, our data show that HNF4a regulates the growth and molecular subtype of PDAC by multiple mechanisms, including activation of the Classical gene expression program and repression of SIX4 and SIX1, which may represent novel dependencies of the Basal-like subtype.

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Section: Discussionmentioning

confidence: 99%

Reciprocal regulation of pancreatic ductal adenocarcinoma growth and molecular subtype by HNF4α and SIX1/4

Camolotto

Belova

Torre-Healy

et al. 2019

Preprint

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“…Accumulated studies have shown that it is still feasible to develop small molecules binding to these targets (Macalino et al, 2018;Das et al, 2019). One strategy is to develop allosteric inhibitors which induce a new binding site to affect function of the target (Anantharajan et al, 2019). FBDD is successful in the development of KRAS inhibitors.…”

Section: Targets With a Shallow Pocketmentioning

confidence: 99%

Application of Fragment-Based Drug Discovery to Versatile Targets

2020

Front. Mol. Biosci.

114

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Fragment-based drug discovery (FBDD) is a powerful method to develop potent smallmolecule compounds starting from fragments binding weakly to targets. As FBDD exhibits several advantages over high-throughput screening campaigns, it becomes an attractive strategy in target-based drug discovery. Many potent compounds/inhibitors of diverse targets have been developed using this approach. Methods used in fragment screening and understanding fragment-binding modes are critical in FBDD. This review elucidates fragment libraries, methods utilized in fragment identification/confirmation, strategies applied in growing the identified fragments into drug-like lead compounds, and applications of FBDD to different targets. As FBDD can be readily carried out through different biophysical and computer-based methods, it will play more important roles in drug discovery.

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“…It has been noted that challenges still remain to develop a small molecule that is able to compete with the hydrophobic molecule in TEAD. A recent study proves that a co-crystal structure of a protein with its ligand is able to expand our knowledge of its function and provides a new strategy to develop inhibitors [85,86]. Nurr1 is an orphan nuclear receptor-a member of NR4A superfamily and important for the development and maintenance of mDA neurons [87].…”

Section: New Druggable Sites and Novel Function Derived From Structuresmentioning

confidence: 99%

“…Lastly, the Tyr activity of EYA proteins might be an important target in cancer therapy as three proteins, including H2AX [153][154][155], estrogen receptor β (ER-β) [156] and WDR1 [157] are substrates of EYA proteins. A recent study indicated that inhibiting the Tyr phosphatase activity of EYA2 affected lung cancer migration and invasion, suggesting that suppressing the enzymatic activity might be a strategy in cancer therapy [86]. Structures of phosphatases indicate that the active site is undruggable, resulting from their shallow and hydrophilic surface that favors bindings to negatively charged substrates.…”

Section: Allosteric Inhibitors For a Phosphatasementioning

confidence: 99%

“…A potent EYA2 inhibitor confirmed by biochemical assay was developed with a IC 50 of 3.0 µM while the inhibitor binding site was not well defined in the absence of a structure [158,159]. A co-crystal structure of EYA2 with the allosteric inhibitor paves a way for developing small molecules against the Tyr phosphatase activity of EYA proteins [86] (Figure 8). The structure revealed the mode of action for the allosteric inhibitor.…”

Section: Allosteric Inhibitors For a Phosphatasementioning

confidence: 99%

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Mechanisms of Action for Small Molecules Revealed by Structural Biology in Drug Discovery

Kang

2020

IJMS

Self Cite

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Small-molecule drugs are organic compounds affecting molecular pathways by targeting important proteins. These compounds have a low molecular weight, making them penetrate cells easily. Small-molecule drugs can be developed from leads derived from rational drug design or isolated from natural resources. A target-based drug discovery project usually includes target identification, target validation, hit identification, hit to lead and lead optimization. Understanding molecular interactions between small molecules and their targets is critical in drug discovery. Although many biophysical and biochemical methods are able to elucidate molecular interactions of small molecules with their targets, structural biology is the most powerful tool to determine the mechanisms of action for both targets and the developed compounds. Herein, we reviewed the application of structural biology to investigate binding modes of orthosteric and allosteric inhibitors. It is exemplified that structural biology provides a clear view of the binding modes of protease inhibitors and phosphatase inhibitors. We also demonstrate that structural biology provides insights into the function of a target and identifies a druggable site for rational drug design.

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Structural and Functional Analyses of an Allosteric EYA2 Phosphatase Inhibitor That Has On-Target Effects in Human Lung Cancer Cells

Cited by 36 publications

References 41 publications

Reciprocal regulation of pancreatic ductal adenocarcinoma growth and molecular subtype by HNF4α and SIX1/4

Reciprocal regulation of pancreatic ductal adenocarcinoma growth and molecular subtype by HNF4α and SIX1/4

Application of Fragment-Based Drug Discovery to Versatile Targets

Mechanisms of Action for Small Molecules Revealed by Structural Biology in Drug Discovery

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