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Dive into the research topics where Saeed R. Khan is active.

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Featured researches published by Saeed R. Khan.


Journal of Medicinal Chemistry | 2003

Design, synthesis, and evaluation of novel boronic-chalcone derivatives as antitumor agents.

Srinivas K. Kumar; Erin R. Hager; Catherine Pettit; Hallur Gurulingappa; Nancy E. Davidson; Saeed R. Khan

A series of boronic-chalcone derivatives were synthesized and tested for antitumor activity against human breast cancer cell lines. The results show the boronic-chalcones are more toxic to breast cancer cells compared to normal breast cells than other known chalcones.


Molecular Pharmacology | 2006

A boronic-chalcone derivative exhibits potent anticancer activity through inhibition of the proteasome

Geetha Achanta; Aneta Modzelewska; Li Feng; Saeed R. Khan; Peng Huang

Chalcones and their derivatives have been shown to have potent anticancer activity. However, the exact mechanisms of cytotoxic activity remain to be established. In this study, we have evaluated a series of boronic chalcones for their anticancer activity and mechanisms of action. Among the eight chalcone derivatives tested, 3,5-bis-(4-boronic acid-benzylidene)-1-methyl-piperidin-4-one (AM114) exhibited most potent growth inhibitory activity with IC50 values of 1.5 and 0.6 μM in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and colony formation assay, respectively. The cytotoxic activity of AM114 was shown to be associated with the accumulation of p53 and p21 proteins and induction of apoptosis. Mechanistic studies showed that AM114 treatment inhibited the chymotrypsin-like activity of the 20S proteasome in vitro, leading to a significant accumulation of ubiquitinated p53 and other cellular proteins in whole cells. In vitro studies showed that AM114 did not significantly disrupt the interaction of p53 and murine double minute 2 protein. It is noteworthy that AM114 as a single agent was preferentially toxic to cells with wild-type p53 expression, whereas combination of this compound with ionizing radiation (IR) significantly enhanced the cell-killing activity of IR in both wild-type p53 and p53-null cells. Together, these results indicate that the boronic chalcone derivative AM114 induces significant cytotoxic effect in cancer cells through the inhibition of the cellular proteasome and provide a rationale for the further development of this class of compounds as novel cancer chemotherapeutic agents.


Cancer Biology & Therapy | 2004

Targeting vascular and avascular compartments of tumors with C. novyi-NT and anti-microtubule agents.

Long H. Dang; Chetan Bettegowda; Nishant Agrawal; Ian Cheong; David L. Huso; Philip Frost; Frank Loganzo; Lee M. Greenberger; Jozsef Barkoczy; George R. Pettit; Amos B. Smith; Hallur Gurulingappa; Saeed R. Khan; Giovanni Parmigiani; Kenneth W. Kinzler; Shibin Zhou; Bert Vogelstein

Current approaches for treating cancer are limited, in part, by the inability of drugs to affect the poorly vascularized regions of tumors. We have found that C. novyi-NT in combination with anti-microtubule agents can cause the destruction of both the vascular and avascular compartments of tumors. The two classes of microtubule inhibitors were found to exert markedly different effects. Some agents that inhibited microtubule synthesis, such as HTI-286 and vinorelbine, caused rapid, massive hemorrhagic necrosis when used in combination with C. novyi-NT. In contrast, agents that stabilized microtubules, such as the taxanes docetaxel and MAC-321, resulted in slow tumor regressions that killed most neoplastic cells. Remaining cells in the poorly perfused regions of tumors could be eradicated by C. novyi-NT. Mechanistic studies showed that the microtubule destabilizers, but not the microtubule stabilizers, radically reduced blood flow to tumors, thereby enlarging the hypoxic niche in which C. novyi-NT spores could germinate. A single intravenous injection of C. novyi-NT plus selected anti-microtubule agents was able to cause regressions of several human tumor xenografts in nude mice in the absence of excessive toxicity.


Journal of Medicinal Chemistry | 2011

α,β-Unsaturated Carbonyl System of Chalcone-Based Derivatives is Responsible for Broad Inhibition of Proteasomal Activity and Preferential Killing of Human Papilloma Virus (HPV)-Positive Cervical Cancer Cells

Martina Bazzaro; Ravi K. Anchoori; Mohana Krishna R Mudiam; Olga A. Issaenko; Srinivas K. Kumar; Balasubramanyam Karanam; Zhenhua Lin; Rachel Isaksson Vogel; Riccardo Gavioli; Federica Destro; Valeria Ferretti; Richard Roden; Saeed R. Khan

Proteasome inhibitors have potential for the treatment of cervical cancer. We describe the synthesis and biological characterization of a new series of 1,3-diphenylpropen-1-one (chalcone) based derivatives lacking the boronic acid moieties of the previously reported chalcone-based proteasome inhibitor 3,5-bis(4-boronic acid benzylidene)-1-methylpiperidin-4-one and bearing a variety of amino acid substitutions on the amino group of the 4-piperidone. Our lead compound 2 (RA-1) inhibits proteasomal activity and has improved dose-dependent antiproliferative and proapoptotic properties in cervical cancer cells containing human papillomavirus. Further, it induces synergistic killing of cervical cancer cell lines when tested in combination with an FDA approved proteasome inhibitor. Exploration of the potential mechanism of proteasomal inhibition by our lead compound using in silico docking studies suggests that the carbonyl group of its oxopiperidine moiety is susceptible to nucleophilic attack by the γ-hydroxythreonine side chain within the catalytic sites of the proteasome.


The Prostate | 2000

In vivo activity of a PSA-activated doxorubicin prodrug against PSA-producing human prostate cancer xenografts.

Saeed R. Khan; Samuel R. Denmeade

There is currently no effective therapy for men with metastatic prostate cancer who relapse after androgen ablation. Prolonged administration of effective concentrations of standard chemotherapeutic agents is usually not possible because of dose‐limiting systemic toxicities. A new strategy to target cytotoxic agents specifically to sites of metastatic prostate cancer while avoiding systemic toxicity would be to develop prodrugs that are inactive when given systemically but become activated when processed proteolytically within prostate cancer metastases by prostate‐specific antigen (PSA). In this study, the in vivo activity of a prodrug consisting of doxorubicin (Dox) conjugated to a PSA‐specific peptide carrier is described.


Bioorganic & Medicinal Chemistry | 2008

Targeted inhibition of hedgehog signaling by cyclopamine prodrugs for advanced prostate cancer

Srinivas K. Kumar; Indrajit Roy; Ravi K. Anchoori; Sarah Fazli; Anirban Maitra; Philip A. Beachy; Saeed R. Khan

A promising agent for use in prostate cancer therapy is the Hedgehog (Hh) signaling pathway inhibitor, cyclopamine. This compound, however, has the potential for causing serious side effects in non-tumor tissues. To minimize these bystander toxicities, we have designed and synthesized two novel peptide-cyclopamine conjugates as prostate-specific antigen (PSA)-activated prodrugs for use against prostate cancer. These prodrugs were composed of cyclopamine coupled to one of two peptides (either HSSKLQ or SSKYQ) that can be selectively cleaved by PSA, converting the mature prodrug into an active Hedgehog inhibitor within the malignant cells. Of the two prodrugs, Mu-SSKYQ-Cyclopamine was rapidly hydrolyzed, with a half-life of 3.2h, upon incubation with the PSA enzyme. Thus, modulating cyclopamine at the secondary amine with PSA-cleavable peptides is a promising strategy for developing prodrugs to target prostate cancer.


Current Medicinal Chemistry - Anti-cancer Agents | 2005

Sesquiterpenes: Natural Products That Decrease Cancer Growth

Aneta Modzelewska; Surojit Sur; Srinivas K. Kumar; Saeed R. Khan

Despite recent advances in our understanding of the biological processes leading to the development of cancer, there is still a need for new and effective agents to help bring this disease under control. One of the oldest and most effective strategies for developing new chemotherapeutics is the isolation and evaluation of chemicals of natural origin. The importance of natural products for drug discovery has been impressive: One has to only look at the number of clinically active drugs that are used in cancer therapy to see how many are either natural products or are based on natural products. It is also apparent that materials from natural sources are excellent probes (indicators) for cellular targets that, when modulated, may have a deleterious effect upon the survival or proliferation of tumor cells. And the search goes on. Sesquiterpenes are a class of naturally occurring molecules that have demonstrated therapeutic potential in decreasing the progression of cancer. These molecules are 15-carbon isoprenoid compounds that are typically found in plants and marine life. Although this class of compounds has frequently provided encouraging leads for chemotherapeutics, they have not been evaluated as potential anticancer agents. In this review, we provide a current overview of sesquiterpenoids that have potential as anticancer agents.


Cancer Biology & Therapy | 2009

Fenugreek: a naturally occurring edible spice as an anticancer agent

Shabana Shabbeer; Michelle Sobolewski; Ravi K. Anchoori; Sushant Kachhap; Manuel Hidalgo; Antonio Jimeno; Nancy E. Davidson; Michael A. Carducci; Saeed R. Khan

In recent years, various dietary components that can potentially be used for the prevention and treatment of cancer have been identified. In this study, we demonstrate that extract (FE) from the seeds of the plant Trigonella foenum graecum, commonly called fenugreek, are cytotoxic in vitro to a panel of cancer but not normal cells. Treatment with 10-15 ug/mL of FE for 72h was growth inhibitory to breast, pancreatic and prostate cancer cell lines (PCa). When tested at higher doses (15-20 ug/mL), FE continued to be growth inhibitory to PCa cell lines but not to either primary prostate or htert-immortalized prostate cells. At least part of the growth inhibition is due to induction of cell death, as seen by incorporation of Ethidium Bromide III into cancer cells exposed to FE. Molecular changes induced in PCa cells are: in DU-145 cells: down regulation of mutant p53, and in PC-3 cells up regulation of p21 and inhibition of TGF-β induced phosphorylation of Akt. The surprising finding of our studies is that death of cancer cells occurs despite growth stimulatory pathways being simultaneously up regulated (phosphorylated) by FE. Thus, these studies add another biologically active agent to our armamentarium of naturally occurring agents with therapeutic potential.


Bioorganic & Medicinal Chemistry Letters | 2002

A 5-fluorodeoxyuridine prodrug as targeted therapy for prostate cancer

Annastasiah Mhaka; Sam Denmeade; Wei Yao; John T. Isaacs; Saeed R. Khan

A method for targeted delivery of the cytotoxic agent 5-fluorodeoxyuridine (FudR) (1) to sites of metastatic prostate cancer is described. The prodrug was synthesized by coupling the active drug (FudR) to the PSA-peptide via a self-cleaving diamino acid linker to produce HSSKLQ-Leu-Aib-FudR. This prodrug serves as a substrate for prostate specific antigen (PSA). This approach permitted efficient conversion of the inactive prodrug back to the active cytotoxic state by the enzymatic activity of PSA which is highly expressed by prostate cells.


PLOS ONE | 2011

Stressing the Ubiquitin-Proteasome System without 20S Proteolytic Inhibition Selectively Kills Cervical Cancer Cells

Ravi K. Anchoori; Saeed R. Khan; Thanasak Sueblinvong; Alicia Felthauser; Yoshie Iizuka; Riccardo Gavioli; Federica Destro; Rachel Isaksson Vogel; Shiwen Peng; Richard Roden; Martina Bazzaro

Cervical cancer cells exhibit an increased requirement for ubiquitin-dependent protein degradation associated with an elevated metabolic turnover rate, and for specific signaling pathways, notably HPV E6-targeted degradation of p53 and PDZ proteins. Natural compounds with antioxidant properties including flavonoids and triterpenoids hold promise as anticancer agents by interfering with ubiquitin-dependent protein degradation. An increasing body of evidence indicates that their α-β unsaturated carbonyl system is the molecular determinant for inhibition of ubiquitin-mediated protein degradation up-stream of the catalytic sites of the 20S proteasome. Herein we report the identification and characterization of a new class of chalcone-based, potent and cell permeable chemical inhibitors of ubiquitin-dependent protein degradation, and a lead compound RAMB1. RAMB1 inhibits ubiquitin-dependent protein degradation without compromising the catalytic activities of the 20S proteasome, a mechanism distinct from that of Bortezomib. Treatment of cervical cancer cells with RAMB1 triggers unfolded protein responses, including aggresome formation and Hsp90 stabilization, and increases p53 steady state levels. RAMB1 treatment results in activation of lysosomal-dependent degradation pathways as a mechanism to compensate for increasing levels of poly-ubiquitin enriched toxic aggregates. Importantly, RAMB1 synergistically triggers cell death of cervical cancer cells when combined with the lysosome inhibitor Chloroquine.

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Manuel Hidalgo

Beth Israel Deaconess Medical Center

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Antonio Jimeno

University of Colorado Denver

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John T. Isaacs

Johns Hopkins University

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Samuel R. Denmeade

Johns Hopkins University School of Medicine

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Bert Vogelstein

Howard Hughes Medical Institute

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David Farquhar

University of Texas MD Anderson Cancer Center

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