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Disease Domain	Count

Neoplasms	1

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Small molecule drug	1

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PP2A(Protein phosphatase 2A)	1

Author: Moriya, Masaaki ; Cohen, Ira ; Dickman, Kathleen G ; Kim, Hwan Keun ; Breslauer, Kenneth J ; Hashimoto, Keiji ; Yin, Xingyu ; Chennamshetti, Rajesh ; Gao, Junyuan ; Minetti, Conceição A ; Garcia-Diaz, Miguel ; Waldeck, Amanda L ; Li, Chaoping ; Grollman, Arthur P ; Bonala, Radha ; Sidorenko, Viktoriya S ; Dorjee, Kunchok ; Hearing, Janet ; Remeta, David P ; Yen, Wan-Yi ; Gupta, Ramesh ; Johnson, Francis ; Potapova, Irina ; Wang, Hong Zhan ; Rosenquist, Thomas A

The emergence of highly infectious pathogens with their potential for triggering global pandemics necessitate the development of effective treatment strategies, including broad-spectrum antiviral therapies to safeguard human health. This study investigates the antiviral activity of emetine, dehydroemetine (DHE), and congeneric compounds against SARS-CoV-2 and HCoV-OC43, and evaluates their impact on the host cell. Concurrently, we assess the potential cardiotoxicity of these ipecac alkaloids. Significantly, our data reveal that emetine and the (-)-R,S isomer of 2,3-dehydroemetine (designated in this paper as DHE4) reduce viral growth at nanomolar concentrations (i.e., IC₅₀ ∼ 50-100 nM), paralleling those required for inhibition of protein synthesis, while calcium channel blocking activity occurs at elevated concentrations (i.e., IC₅₀ ∼ 40-60 µM). Our findings suggest that the antiviral mechanisms primarily involve disruption of host cell protein synthesis and is demonstrably stereoisomer specific. The prospect of a therapeutic window in which emetine or DHE4 inhibit viral propagation without cardiotoxicity renders these alkaloids viable candidates in strategies worthy of clinical investigation.

01 Oct 2014·Journal of Enzyme Inhibition and Medicinal ChemistryQ2 · MEDICINE

Inhibition of anthrax lethal factor by curcumin and chemically modified curcumin derivatives

Q2 · MEDICINE

ArticleOA

Author: Golub, Lorne M. ; Zhang, Yu ; Antonelli, Anthony C. ; Simon, Sanford R. ; Johnson, Francis

Curcumin (diferuloylmethane), the active ingredient in the eastern spice turmeric (Curcuma longa), has been shown to inhibit the activities of numerous enzymes and signaling molecules involved in cancer, bacterial and viral infections and inflammatory diseases. We have investigated the inhibitory activities of curcumin and chemically modified curcumin (CMC) derivatives toward lethal factor (LF), the proteolytic component of anthrax toxin produced by the bacterium Bacillus anthracis. Curcumin (Compound 1) appears to inhibit the catalytic activity of LF through a mixture of inhibitory mechanisms, without significant compromise to the binding of oligopeptide substrates, and one CMC derivative in particular, Compound 3 (4-phenylaminocarbonylbis-demethoxycurcumin), is capable of inhibiting LF with potency comparable with the parent compound, while also showing improved solubility and stability. The quantitative reduction in catalytic activity achieved by the different CMC derivatives appears to be a function of the proportion of the multiple mechanisms through which they inhibit the enzyme.

14 Jul 2009·Proceedings of the National Academy of SciencesQ1 · CROSS-FIELD

Inhibition of serine/threonine phosphatase PP2A enhances cancer chemotherapy by blocking DNA damage induced defense mechanisms

Q1 · CROSS-FIELD

Article

Author: Hodes, Richard ; Lu, Jie ; Zhuang, Zhengping ; Chiang, Jeffrey ; Kovach, John S. ; Johnson, Francis ; Lonser, Russell

A variety of mechanisms maintain the integrity of the genome in the face of cell stress. Cancer cell response to chemotherapeutic and radiation-induced DNA damage is mediated by multiple defense mechanisms including polo-like kinase 1 (Plk-1), protein kinase B (Akt-1), and/or p53 pathways leading to either apoptosis or cell cycle arrest. Subsequently, a subpopulation of arrested viable cancer cells may remain and recur despite aggressive and repetitive therapy. Here, we show that modulation (activation of Akt-1 and Plk-1 and repression of p53) of these pathways simultaneously results in paradoxical enhancement of the effectiveness of cytotoxic chemotherapy. We demonstrate that a small molecule inhibitor, LB-1.2, of protein phosphatase 2A (PP2A) activates Plk-1 and Akt-1 and decreases p53 abundance in tumor cells. Combined with temozolomide (TMZ; a DNA-methylating chemotherapeutic drug), LB-1.2 causes complete regression of glioblastoma multiforme (GBM) xenografts without recurrence in 50% of animals (up to 28 weeks) and complete inhibition of growth of neuroblastoma (NB) xenografts. Treatment with either drug alone results in only short-term inhibition/regression with all xenografts resuming rapid growth. Combined with another widely used anticancer drug, Doxorubicin (DOX, a DNA intercalating agent), LB-1.2 also causes marked GBM xenograft regression, whereas DOX alone only slows growth. Inhibition of PP2A by LB-1.2 blocks cell-cycle arrest and increases progression of cell cycle in the presence of TMZ or DOX. Pharmacologic inhibition of PP2A may be a general method for enhancing the effectiveness of cancer treatments that damage DNA or disrupt components of cell replication.

100 Deals associated with CHEM-MASTER INTERNATIONAL Inc

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100 Translational Medicine associated with CHEM-MASTER INTERNATIONAL Inc

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Pipeline

Pipeline Snapshot as of 29 Dec 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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