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Dive into the research topics where Brendan Frett is active.

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Featured researches published by Brendan Frett.


Journal of Medicinal Chemistry | 2013

Targeting Mutant KRAS for Anticancer Therapeutics: A Review of Novel Small Molecule Modulators

Yuanxiang Wang; Christine E. Kaiser; Brendan Frett; Hong Yu Li

The RAS proteins play a role in cell differentiation, proliferation, and survival. Aberrant RAS signaling has been found to play a role in 30% of all cancers. KRAS, a key member of the RAS protein family, is an attractive cancer target, as frequent point mutations in the KRAS gene render the protein constitutively active. A number of attempts have been made to target aberrant KRAS signaling by identifying small molecule compounds that (1) are synthetic lethal to mutant KRAS, (2) block KRAS/GEF interactions, (3) inhibit downstream KRAS effectors, or (4) inhibit the post-translational processing of RAS proteins. In addition, inhibition of novel targets outside the main KRAS signaling pathway, specifically the cell cycle related kinase PLK1, has been shown have an effect in cells that harbor mutant KRAS. Herein we review the use of various high-throughput screening assays utilized to identify new small-molecule compounds capable of targeting mutant KRAS-driven cancers.


Organic Letters | 2014

Efficient Access to 2,3-Diarylimidazo[1,2-a]pyridines via a One-Pot, Ligand-Free, Palladium-Catalyzed Three-Component Reaction under Microwave Irradiation

Yuanxiang Wang; Brendan Frett; Hong Yu Li

An expeditious one-pot, ligand-free, Pd(OAc)2-catalyzed, three-component reaction for the synthesis of 2,3-diarylimidazo[1,2-a]pyridines was developed under microwave irradiation. With the high availability of commercial reagents and great efficiency in expanding molecule diversity, this methodology is superior to the existing procedures for the synthesis of 2,3-diarylimidazo[1,2-a]pyridines analogues.


Organic and Biomolecular Chemistry | 2015

Metal-free, efficient hydrazination of imidazo[1,2-a]pyridine with diethyl azodicarboxylate in neutral media.

Yuanxiang Wang; Brendan Frett; Nick McConnell; Hong Yu Li

The first example of metal-free regioselective hydrazination of imidazo[1,2-a]pyridine with diethyl azodicarboxylate is accomplished. This procedure is chemically appealing due to the high degree of functional group tolerance and efficiency in expanding the molecular diversity.


Journal of Medicinal Chemistry | 2014

Therapeutic Melting Pot of Never in Mitosis Gene A Related Kinase 2 (Nek2): A Perspective on Nek2 as an Oncology Target and Recent Advancements in Nek2 Small Molecule Inhibition

Brendan Frett; Robert V. Brown; Ming-Liang Ma; Wenhao Hu; Haiyong Han; Hong Yu Li

The global incidence of cancer is on the rise, and within the next decade, the disease is expected to become the leading cause of death worldwide. Forthcoming strategies used to treat cancers focus on the design and implementation of multidrug therapies to target complementary cancer specific pathways. A more direct means by which this multitargeted approach can be achieved is by identifying and targeting interpathway regulatory factors. Recent advances in understanding Nek2 (NIMA related kinase 2) biology suggest that the kinase potentially represents a multifaceted therapeutic target. In this regard, pharmacologic modulation of Nek2 with a single agent may effect several mechanisms important for tumor growth, survival, progression, and metastasis. We herein review the development of Nek2 as an oncology target and provide a succinct chronology of drug discovery campaigns focused on targeting Nek2.


Journal of Clinical Investigation | 2017

Targeting NEK2 attenuates glioblastoma growth and radioresistance by destabilizing histone methyltransferase EZH2

Jia Wang; Peng Cheng; Marat S. Pavlyukov; Hai Yu; Zhuo Zhang; Sung Hak Kim; Mutsuko Minata; Ahmed Mohyeldin; Wanfu Xie; Dongquan Chen; Violaine Goidts; Brendan Frett; Wenhao Hu; Hong-yu Li; Yong Jae Shin; Yeri Lee; Do Hyun Nam; Harley I. Kornblum; Maode Wang; Ichiro Nakano

Accumulating evidence suggests that glioma stem cells (GSCs) are important therapeutic targets in glioblastoma (GBM). In this study, we identified NIMA-related kinase 2 (NEK2) as a functional binding protein of enhancer of zeste homolog 2 (EZH2) that plays a critical role in the posttranslational regulation of EZH2 protein in GSCs. NEK2 was among the most differentially expressed kinase-encoding genes in GSC-containing cultures (glioma spheres), and it was required for in vitro clonogenicity, in vivo tumor propagation, and radioresistance. Mechanistically, the formation of a protein complex comprising NEK2 and EZH2 in glioma spheres phosphorylated and then protected EZH2 from ubiquitination-dependent protein degradation in a NEK2 kinase activity–dependent manner. Clinically, NEK2 expression in patients with glioma was closely associated with EZH2 expression and correlated with a poor prognosis. NEK2 expression was also substantially elevated in recurrent tumors after therapeutic failure compared with primary untreated tumors in matched GBM patients. We designed a NEK2 kinase inhibitor, compound 3a (CMP3a), which efficiently attenuated GBM growth in a mouse model and exhibited a synergistic effect with radiotherapy. These data demonstrate a key role for NEK2 in maintaining GSCs in GBM by stabilizing the EZH2 protein and introduce the small-molecule inhibitor CMP3a as a potential therapeutic agent for GBM.


European Journal of Medicinal Chemistry | 2015

Computer aided drug discovery of highly ligand efficient, low molecular weight imidazopyridine analogs as FLT3 inhibitors

Brendan Frett; Nick McConnell; Catherine C. Smith; Yuanxiang Wang; Neil P. Shah; Hong Yu Li

The FLT3 kinase represents an attractive target to effectively treat AML. Unfortunately, no FLT3 targeted therapeutic is currently approved. In line with our continued interests in treating kinase related disease for anti-FLT3 mutant activity, we utilized pioneering synthetic methodology in combination with computer aided drug discovery and identified low molecular weight, highly ligand efficient, FLT3 kinase inhibitors. Compounds were analyzed for biochemical inhibition, their ability to selectively inhibit cell proliferation, for FLT3 mutant activity, and preliminary aqueous solubility. Validated hits were discovered that can serve as starting platforms for lead candidates.


European Journal of Medicinal Chemistry | 2014

Identification of two novel RET kinase inhibitors through MCR-based drug discovery: Design, synthesis and evaluation

Brendan Frett; Marialuisa Moccia; Francesca Carlomagno; Massimo Santoro; Hong Yu Li

From an MCR fragment library, two novel chemical series have been developed as inhibitors of RET, which is a kinase involved in the pathology of medullary thyroid cancer (MTC). Structure activity relationship studies (SAR) identified two sub-micromolar tractable leads, 6g and 13g. 6g was confirmed to be a Type-II RET inhibitor. 13g and 6g inhibited RET in cells transformed by RET/C634. A RET DFG-out homology model was established and utilized to predict Type-II inhibitor binding modes.


MedChemComm | 2014

Identification of pyrazine-based TrkA inhibitors: design, synthesis, evaluation, and computational modeling studies

Brendan Frett; Nick McConnell; Yuanxiang Wang; Zhigang Xu; Andrew J. Ambrose; Hong Yu Li

Trk receptors play a key role in the development and maintenance of neuronal networks. Recent evidence suggests that the Trk family, specifically TrkA, is an important driver for tumour growth, inflammatory and neuropathic pain, and chemoresistance. Through a computational screen, a novel Trk active pharmacophore was identified and a series of pyrazine-based inhibitors were developed, which potently inhibited TrkA. Inhibitors displayed the highest activity on TrkA when screened against a small, tyrosine kinase panel and also exhibited a non-linear SAR. Predicted binding modes of the inhibitors were examined, which identified exploitable regions for future development of more advanced inhibitors.


ChemMedChem | 2013

Targeting the K‐Ras/PDEδ Protein–Protein Interaction: The Solution for Ras‐Driven Cancers or Just Another Therapeutic Mirage?

Brendan Frett; Yuanxiang Wang; Hong Yu Li

The holy grail, finally? After years of unsuccessful attempts at drugging the Ras oncogene, a recent paper by Zimmerman et al. has revealed the possibility of inhibiting Ras signaling on a clinically relevant level by blocking the K-Ras/PDEδ protein-protein interaction. The results, reported in Nature, are highlighted herein with future implications and directions to evaluate the full clinical potential of this research.


Tetrahedron | 2018

Selective, C-3 Friedel-Crafts acylation to generate functionally diverse, acetylated Imidazo[1,2-a]pyridine derivatives

Brendan Frett; Nicholas McConnell; Anupreet Kharbanda; Gunaganti Naresh; Benjamin Rounseville; Christina Warner; John Chang; Natalie Debolske; Hong Yu Li

Carbon-carbon bonds are integral for pharmaceutical discovery and development. Frequently, C-C bond reactions utilize expensive catalyst/ligand combinations and/or are low yielding, which can increase time and expenditures in pharmaceutical development. To enhance C-C bond formation protocols, we developed a highly efficient, selective, and combinatorially applicable Friedel-Crafts acylation to acetylate the C-3 position of imidazo[1,2-a]pyridines. The reaction, catalyzed by aluminum chloride, is both cost effective and more combinatorial friendly compared to acetylation reactions requiring multiple, stoichiometric equivalents of AlCl3. The protocol has broad application in the construction of acetylated imidazo[1,2-a]pyridines with an extensive substrate scope. All starting materials are common and the reaction requires inexpensive, conventional heating methods for adaptation in any laboratory. Further, the synthesized compounds are predicted to possess GABA activity through a validated, GABA binding model. The developed method serves as a superior route to generate C-3 acetylated imidazo[1,2-a]pyridine building-blocks for combinatorial synthetic efforts.

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Hong-yu Li

University of Arkansas for Medical Sciences

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Francesca Carlomagno

University of Naples Federico II

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