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Dive into the research topics where Chang-Sun Lee is active.

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Featured researches published by Chang-Sun Lee.


Journal of Medicinal Chemistry | 2016

Discovery and Optimization of Small Molecule Splicing Modifiers of Survival Motor Neuron 2 as a Treatment for Spinal Muscular Atrophy

Matthew G. Woll; Hongyan Qi; Anthony Turpoff; Nanjing Zhang; Xiaoyan Zhang; Guangming Chen; Chunshi Li; Song Huang; Tianle Yang; Young-Choon Moon; Chang-Sun Lee; Soongyu Choi; Neil Gregory Almstead; Nikolai Naryshkin; Amal Dakka; Jana Narasimhan; Vijayalakshmi Gabbeta; Ellen Welch; Xin Zhao; Nicole Risher; Josephine Sheedy; Marla Weetall; Gary Mitchell Karp

The underlying cause of spinal muscular atrophy (SMA) is a deficiency of the survival motor neuron (SMN) protein. Starting from hits identified in a high-throughput screening campaign and through structure-activity relationship investigations, we have developed small molecules that potently shift the alternative splicing of the SMN2 exon 7, resulting in increased production of the full-length SMN mRNA and protein. Three novel chemical series, represented by compounds 9, 14, and 20, have been optimized to increase the level of SMN protein by >50% in SMA patient-derived fibroblasts at concentrations of <160 nM. Daily administration of these compounds to severe SMA Δ7 mice results in an increased production of SMN protein in disease-relevant tissues and a significant increase in median survival time in a dose-dependent manner. Our work supports the development of an orally administered small molecule for the treatment of patients with SMA.


Cancer Research | 2014

Abstract 5517: PTC596-induced Bmi1 hyper-phosphorylation via Cdk1/2 activation resulting in tumor stem cell depletion

Min Jung Kim; Liangxian Cao; Josephine Sheedy; Nicole Risher; Melissa Dumble; Chang-Sun Lee; Nadiya Sydorenko; Ramil Baiazitov; Wu Du; Young-Choon Moon; Marla Weetall; Joseph M. Colacino; Thomas W. Davis

The Polycomb group (PcG) transcription repressor BMI1 is highly expressed in human cancers and is required for the clonogenic self-renewal and tumorigenesis of human cancer cells including those in hematological cancer and neuroblastoma. PTC596 is efficacious in vivo across a range of xenograft tumor models, including models of glioblastoma, fibrosarcoma and leukemia as well as orthotopic models of GBM. With EC50 values of 30-200 nM in a variety of tumor cell lines, PTC596 selectively reduces the level of functional BMI1 protein resulting in the depletion of the tumor stem cell fraction. PTC596 induces the hyper-phosphorylation of BMI1 leading to its degradation and the reduction of polycomb repressive complex 1 (PRC1) activity. Mechanistic studies suggest that PTC596 inhibits APC/CCDC20 activity resulting in the persistent activation of CDK1 and CDK2 which mediate the hyperphosphorylation of BMI1. Studies are ongoing to elucidate the mechanism of PTC596 inhibition of APC/CCDC20 and its preferential depletion of the tumor stem cell fraction. Citation Format: Min Jung Kim, Liangxian Cao, Josephine Sheedy, Nicole Risher, Melissa Dumble, Chang-Sun Lee, Nadiya Sydorenko, Ramil Baiazitov, Wu Du, Young-Choon Moon, Marla L. Weetall, Joseph Colacino, Thomas W. Davis. PTC596-induced Bmi1 hyper-phosphorylation via Cdk1/2 activation resulting in tumor stem cell depletion. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5517. doi:10.1158/1538-7445.AM2014-5517


Oncogene | 2018

BMI1 is a therapeutic target in recurrent medulloblastoma

David Bakhshinyan; Chitra Venugopal; Ashley Adile; Neha Garg; Branavan Manoranjan; Robin M. Hallett; Xin Wang; Sujeivan Mahendram; Parvez Vora; Thusyanth Vijayakumar; Minomi Subapanditha; Mohini Singh; Michelle Kameda-Smith; Maleeha Qazi; Nicole McFarlane; Aneet Mann; Olufemi Ajani; Blake Yarascavitch; Vijay Ramaswamy; Hamza Farooq; Sorana Morrissy; Liangxian Cao; Nadiya Sydorenko; Ramil Baiazitov; Wu Du; Josephine Sheedy; Marla Weetall; Young-Choon Moon; Chang-Sun Lee; Jacek M. Kwiecien

Medulloblastoma (MB) is the most frequent malignant pediatric brain tumor, representing 20% of newly diagnosed childhood central nervous system malignancies. Although advances in multimodal therapy yielded a 5-year survivorship of 80%, MB still accounts for the leading cause of childhood cancer mortality. In this work, we describe the epigenetic regulator BMI1 as a novel therapeutic target for the treatment of recurrent human Group 3 MB, a childhood brain tumor for which there is virtually no treatment option beyond palliation. Current clinical trials for recurrent MB patients based on genomic profiles of primary, treatment-naive tumors will provide limited clinical benefit since recurrent metastatic MBs are highly genetically divergent from their primary tumor. Using a small molecule inhibitor against BMI1, PTC-028, we were able to demonstrate complete ablation of self-renewal of MB stem cells in vitro. When administered to mice xenografted with patient tumors, we observed significant reduction in tumor burden in both local and metastatic compartments and subsequent increased survival, without neurotoxicity. Strikingly, serial in vivo re-transplantation assays demonstrated a marked reduction in tumor initiation ability of recurrent MB cells upon re-transplantation of PTC-028-treated cells into secondary recipient mouse brains. As Group 3 MB is often metastatic and uniformly fatal at recurrence, with no current or planned trials of targeted therapy, an efficacious targeted agent would be rapidly transitioned to clinical trials.


Cancer Research | 2014

Abstract 2528: Optimization of small molecules targeting BMI1 protein expression. Part 2. Improved potency, oral bioavailability, and in vivo efficacy of amino-pyrazines and amino-pyridines

Ramil Baiazitov; Nadiya Sydorenko; Hongyu Ren; Wu Du; Steve Paget; Richard Gerald Wilde; Ronggang Liu; Chang-Sun Lee; Liangxian Cao; Thomas W. Davis; Neil Gregory Almstead; Young-Choon Moon

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Earlier, in our efforts to identify molecules that selectively deplete tumor stem cells, we discovered and elaborated on a series of amino-thiazoles. These first-in-class small molecule inhibitors reduce the activity and levels of BMI1 protein in vitro and in vivo (see the preceding poster). Through our medicinal chemistry efforts, we developed a second generation of molecules that reduce levels of BMI1. In this new scaffold, the central thiazole ring has been replaced with a pyrazine or pyridine ring. There is a clear relationship between the structure of the central heterocycle and the ability of the compound to decrease the level of BMI1 protein. The most beneficial modification on the right wing of the molecule is the introduction of benzimidazole moiety. As a result, analogs with markedly improved oral bioavailability have been identified. The structure activity relationship on the left ring parallels the SAR observed with the amino-thiazole scaffold. The most successful analogs in this series can be dosed orally and demonstrate dose-dependent efficacy in mouse xenograft models including the HT1080 and L1210 cell lines. Citation Format: Ramil Baiazitov, Nadiya Sydorenko, Hongyu Ren, Wu Du, Steve Paget, Richard Wilde, Ronggang Liu, Chang-Sun Lee, Liangxian Cao, Thomas W. Davis, Neil G. Almstead, Young-Choon Moon. Optimization of small molecules targeting BMI1 protein expression. Part 2. Improved potency, oral bioavailability, and in vivo efficacy of amino-pyrazines and amino-pyridines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2528. doi:10.1158/1538-7445.AM2014-2528


Cancer Research | 2014

Abstract 2529: Optimization of small molecules targeting BMI1 protein expression. Part 1. Amino-thiazoles: the first-in-class highly potent inhibitors of BMI1 protein

Nadiya Sydorenko; Ramil Baiazitov; Soongyu Choi; Chang-Sun Lee; Liangxian Cao; Thomas W. Davis; Neil Gregory Almstead; Young-Choon Moon

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA BMI1 (B-cell specific Moloney Murine Leukemia Virus Insertion 1) is a gene predominantly expressed in stem cells. A deficiency of BMI1 protein leads to a reduction in the adult stem cell population. Decreasing of BMI1 protein levels by siRNA causes apoptosis and/or senescence in tumor cells in vitro and increases susceptibility to cytotoxic agents. In tumors, the level of BMI1 protein is often elevated. Consequently, the expression level of BMI1 is highly prognostic in many types of cancers. Since BMI1 is non-enzymatic, targeting this protein by traditional drug discovery approaches has not met with success. PTC Therapeutics has developed a novel screening technology referred to as GEMSTM (Gene Expression Modulation by Small molecules) to identify small molecules that modulate the levels of a protein of interest by targeting post-transcriptional regulatory processes. Using this screening technology, we have identified a number of compounds that can selectively reduce levels of BMI1 protein. Schematically, the lead scaffold could be represented by four key components: a bicyclic right core, a heterocyclic middle ring (thiazole), a linking group and a left aryl region. Structure-activity relationships associated with this series have been investigated through medicinal chemistry efforts. Incorporation of a small electron-donating para- substituent at the left part of the molecule is highly effective in decreasing levels of BMI1, indicating the strong influence of both steric and electronic effects on activity. An amino (linking group) moiety was found to be essential for activity. Variation at the right-hand moiety appears to be more tolerated, allowing improvements in both pharmacokinetic and activity profiles. These SAR findings have revealed important pharmacophoric and structural features required for the desired biological activity with this series, and provide a foundation for further lead optimization efforts. Citation Format: Nadiya Sydorenko, Ramil Baiazitov, Soongyu Choi, Chang-Sun Lee, Liangxian Cao, Thomas W. Davis, Neil G. Almstead, Young-Choon Moon. Optimization of small molecules targeting BMI1 protein expression. Part 1. Amino-thiazoles: the first-in-class highly potent inhibitors of BMI1 protein. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2529. doi:10.1158/1538-7445.AM2014-2529


Science | 2014

SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy

Nikolai Naryshkin; Marla Weetall; Amal Dakka; Jana Narasimhan; Xin Zhao; Zhihua Feng; Karen K. Y. Ling; Gary Mitchell Karp; Hongyan Qi; Matthew G. Woll; Guangming Chen; Nanjing Zhang; Vijayalakshmi Gabbeta; Priya Vazirani; Anuradha Bhattacharyya; Bansri S. Furia; Nicole Risher; Josephine Sheedy; Ronald Kong; Jiyuan Ma; Anthony Turpoff; Chang-Sun Lee; Xiaoyan Zhang; Young-Choon Moon; Panayiota Trifillis; Ellen Welch; Joseph M. Colacino; John Babiak; Neil G. Almstead; Stuart W. Peltz


Archive | 2013

Compounds for treating spinal muscular atrophy

Chang-Sun Lee; Soongyu Choi; Gary Mitchell Karp; Hiroo Koyama; Hasane Ratni


Synthesis | 2013

Chemoselective Reactions of 4,6-Dichloro-2-(methylsulfonyl)pyrimidine and Related Electrophiles with Amines

Ramil Baiazitov; Wu Du; Chang-Sun Lee; Seongwoo Hwang; Neil G. Almstead; Young-Choon Moon


Archive | 2013

Substituted reverse pyrimidine bmi-1 inhibitors

Chang-Sun Lee; Ramil Baiazitov; Liangxian Cao; Thomas W. Davis; Wu Du; Ronggang Liu; Young-Choon Moon; Steven D. Paget; Hongyu Ren; Nadiya Sydorenko; Richard Gerald Wilde


Archive | 2015

SUBSTITUTED TRIAZINE BMI-1 INHIBITORS

Hiroo Koyama; Ramil Baiazitov; Wu Du; Chang-Sun Lee; Young-Choon Moon; Steven D. Paget; Hongyu Ren; Nadiya Sydorenko

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Thomas W. Davis

University of Wisconsin-Madison

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Josephine Sheedy

Children's Hospital of Philadelphia

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Ellen Welch

University of Medicine and Dentistry of New Jersey

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