Publications by authors named "Fengping Lv"

10 Publications

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Ubiquitination-mediated degradation of TRDMT1 regulates homologous recombination and therapeutic response.

NAR Cancer 2021 Mar 22;3(1):zcab010. Epub 2021 Mar 22.

Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.

The RNA methyltransferase TRDMT1 has recently emerged as a key regulator of homologous recombination (HR) in the transcribed regions of the genome, but how it is regulated and its relevance in cancer remain unknown. Here, we identified that TRDMT1 is poly-ubiquitinated at K251 by the E3 ligase TRIM28, removing TRDMT1 from DNA damage sites and allowing completion of HR. Interestingly, K251 is adjacent to G155 in the 3D structure, and the G155V mutation leads to hyper ubiquitination of TRDMT1, reduced TRDMT1 levels and impaired HR. Accordingly, a TRDMT1 G155V mutation in an ovarian cancer super responder to platinum treatment. Cells expressing TRDMT1-G155V are sensitive to cisplatin and . In contrast, high expression of TRDMT1 in patients with ovarian cancer correlates with platinum resistance. A potent TRDMT1 inhibitor resensitizes TRDMT1-high tumor cells to cisplatin. These results suggest that TRDMT1 is a promising therapeutic target to sensitize ovarian tumors to platinum therapy.
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http://dx.doi.org/10.1093/narcan/zcab010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984809PMC
March 2021

Discovery of pyrazolo-thieno[3,2-d]pyrimidinylamino-phenyl acetamides as type-II pan-tropomyosin receptor kinase (TRK) inhibitors: Design, synthesis, and biological evaluation.

Eur J Med Chem 2021 Apr 9;216:113265. Epub 2021 Feb 9.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA. Electronic address:

Tropomyosin receptor kinase (TRK) represents an attractive oncology target for cancer therapy related to its critical role in cancer formation and progression. NTRK fusions are found to occur in 3.3% of lung cancers, 2.2% of colorectal cancers, 16.7% of thyroid cancers, 2.5% of glioblastomas, and 7.1% of pediatric gliomas. In this paper, we described the discovery of the type-II pan-TRK inhibitor 4c through the structure-based drug design strategy from the original hits 1b and 2b. Compound 4c exhibited excellent in vitro TRKA, TRKB, and TRKC kinase inhibitory activity and anti-proliferative activity against human colorectal carcinoma derived cell line KM12. In the NCI-60 human cancer cell lines screen, compound 4g demonstrated nearly 80% of growth inhibition for KM12, while only minimal inhibitory activity was observed for the remaining 59 cancer cell lines. Western blot analysis demonstrated that 4c and its urea cousin 4k suppressed the TPM3-TRKA autophosphorylation at the concentrations of 100 nM and 10 nM, respectively. The work presented that 2-(4-(thieno[3,2-d]pyrimidin-4-ylamino)phenyl)acetamides could serve as a novel scaffold for the discovery and development of type-II pan-TRK inhibitors for the treatment of TRK driven cancers.
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http://dx.doi.org/10.1016/j.ejmech.2021.113265DOI Listing
April 2021

Insights into Current Tropomyosin Receptor Kinase (TRK) Inhibitors: Development and Clinical Application.

J Med Chem 2019 02 19;62(4):1731-1760. Epub 2018 Sep 19.

Department of Pharmaceutical Sciences, College of Pharmacy , University of Arkansas for Medical Sciences , Little Rock , Arkansas 72205 , United States.

The use of kinase-directed precision medicine has been heavily pursued since the discovery and development of imatinib. Annually, it is estimated that around ∼20 000 new cases of tropomyosin receptor kinase (TRK) cancers are diagnosed, with the majority of cases exhibiting a TRK genomic rearrangement. In this Perspective, we discuss current development and clinical applications for TRK precision medicine by providing the following: (1) the biological background and significance of the TRK kinase family, (2) a compilation of known TRK inhibitors and analysis of their cocrystal structures, (3) an overview of TRK clinical trials, and (4) future perspectives for drug discovery and development of TRK inhibitors.
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http://dx.doi.org/10.1021/acs.jmedchem.8b01092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875308PMC
February 2019

New peptide deformylase inhibitors design, synthesis and pharmacokinetic assessment.

Bioorg Med Chem Lett 2016 08 27;26(15):3714-8. Epub 2016 May 27.

Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, North Zhongshan Road 3663, Shanghai, China. Electronic address:

The docking approach for the screening of designed small molecule ligands, led to the identification of a critical arginine residue in peptide deformylase for spiro cyclopropyl PDF inhibitor's extra hydrophobic binding, providing us a useful tool for searching more efficient PDF inhibitors to fight for horrifying antibiotics resistance. Further synthetic modification was undertaken to optimize the potency of amide compounds. To lower metabolic susceptibility and in turn reduce unwanted metabolic toxicity that was observed clinically, while retaining desired antibacterial activity, the use of azoles as amide bioisosteres had also been investigated. After the completion of chemical synthesis, all the compounds were evaluated through in vitro antibacterial activity assay, some of which were further subject to in vivo rat pharmacokinetic assessment. Those findings in this letter showed that spiro cyclopropyl proline N-formyl hydroxylamines, and especially the bioisosteric azoles, can represent a promising class of PDF inhibitors.
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http://dx.doi.org/10.1016/j.bmcl.2016.05.077DOI Listing
August 2016

Small molecules enhance functional O-mannosylation of Alpha-dystroglycan.

Bioorg Med Chem 2015 Dec 12;23(24):7661-70. Epub 2015 Nov 12.

Mannan Pharmaceuticals LLC, 900B W. Faris Road Suite 700, Greenville, SC 29605, USA; Roc Institute for Arts and Sciences, 1632 Penderlea Lane, NC 28105, USA. Electronic address:

Alpha-dystroglycan (α-DG), a highly glycosylated receptor for extracellular matrix proteins, plays a critical role in many biological processes. Hypoglycosylation of α-DG results in various types of muscular dystrophies and is also highly associated with progression of majority of cancers. Currently, there are no effective treatments for those devastating diseases. Enhancing functional O-mannosyl glycans (FOG) of α-DG on the cell surfaces is a potential approach to address this unmet challenge. Based on the hypothesis that the cells can up-regulate FOG of α-DG in response to certain chemical stimuli, we developed a cell-based high-throughput screening (HTS) platform for searching chemical enhancers of FOG of α-DG from a large chemical library with 364,168 compounds. Sequential validation of the hits from a primary screening campaign and chemical works led to identification of a cluster of compounds that positively modulate FOG of α-DG on various cell surfaces including patient-derived myoblasts. These compounds enhance FOG of α-DG by almost ten folds, which provide us powerful tools for O-mannosylation studies and potential starting points for the development of drug to treat dystroglycanopathy.
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http://dx.doi.org/10.1016/j.bmc.2015.11.011DOI Listing
December 2015

Synthesis, antibacterial activity, and biological evaluation of formyl hydroxyamino derivatives as novel potent peptide deformylase inhibitors against drug-resistant bacteria.

Eur J Med Chem 2014 Oct 12;86:133-52. Epub 2014 Aug 12.

Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Department of Chemistry, East China Normal University, Shanghai 200062, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address:

Peptide deformylase (PDF) has been identified as a promising target for novel antibacterial agents. In this study, a series of novel formyl hydroxyamino derivatives were designed and synthesized as PDF inhibitors and their antibacterial activities were evaluated. Among the potent PDF inhibitors (1o, 1q, 1o', 1q', and 1x), in vivo studies showed that compound 1q possesses mild toxicity, a good pharmacokinetic profile and protective effects. The good in vivo efficacy and low toxicity suggest that this class of compounds has potential for development and use in future antibacterial drugs.
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http://dx.doi.org/10.1016/j.ejmech.2014.07.106DOI Listing
October 2014

Enantioselective trapping of phosphoramidate ammonium ylides with imino esters for synthesis of 2,3-diaminosuccinic acid derivatives.

Chem Commun (Camb) 2013 May 29;49(39):4238-40. Epub 2013 Jan 29.

Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, East China Normal University, 3663 North Zhongshan Rd., Shanghai, 200062, China.

A highly enantioselective trapping of protic phosphoramidate ammonium ylides with α-imino esters is reported. The intriguing Rh2(OAc)4 and chiral Brønsted acid co-catalyzed three-component Mannich-type reaction of a diazo compound, a phosphoramidate, and an α-imino ester provides a rapid and efficient access to 2,3-diaminosuccinic acid derivatives with a high level control of diastereo- and enantioselectivity.
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http://dx.doi.org/10.1039/c3cc36972bDOI Listing
May 2013

Highly diastereoselective multicomponent cascade reactions: efficient synthesis of functionalized 1-indanols.

Angew Chem Int Ed Engl 2013 Jan 20;52(5):1539-42. Epub 2012 Dec 20.

Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, East China Normal University, Shanghai, 200062, China.

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http://dx.doi.org/10.1002/anie.201208391DOI Listing
January 2013