Tumor-Activated Benzothiazole Inhibitors of Stearoyl-CoA Desaturase.

A series of -acyl benzothiazoles shows selective and potent cytotoxicity against cancer cell lines expressing cytochrome P450 4F11. A prodrug form is metabolized by cancer cells into an active inhibitor of stearoyl-CoA desaturase (SCD). Substantial variation on the acyl portion of the inhibitors allowed the identification of ()-, which balanced potency, solubility, and lipophilicity to allow proof-of-concept studies in mice.

Discovery and Characterization of Dual Inhibitors of MDM2 and NFAT1 for Pancreatic Cancer Therapy.

Overexpression and activation of the murine double minute 2 (MDM2) or nuclear factor of activated T cells 1 (NFAT1) oncoproteins frequently occur in pancreatic cancer. Most MDM2 inhibitors under development target MDM2-p53 binding and have little or no effect on cancers without functional p53, including pancreatic cancer. Some available compounds indirectly inhibit NFAT1 activity by interfering with calcineurin activity, but there are currently no specific inhibitors against NFAT1.

Chemistry-First Approach for Nomination of Personalized Treatment in Lung Cancer.

Diversity in the genetic lesions that cause cancer is extreme. In consequence, a pressing challenge is the development of drugs that target patient-specific disease mechanisms. To address this challenge, we employed a chemistry-first discovery paradigm for de novo identification of druggable targets linked to robust patient selection hypotheses.

Inhibitors of 15-Prostaglandin Dehydrogenase To Potentiate Tissue Repair.

The enzyme 15-prostaglandin dehydrogenase (15-PGDH) catalyzes the first step in the degradation of prostaglandins including PGE2. It is a negative regulator of tissue repair and regeneration in multiple organs. Accordingly, inhibitors of 15-PGDH are anticipated to elevate in vivo levels of PGE2 and to promote healing and tissue regeneration.

Identification of lineariifolianoid A as a novel dual NFAT1 and MDM2 inhibitor for human cancer therapy.

There is an increasing interest in development of novel anticancer agents that target oncogenes. We have recently discovered that nuclear factor of activated T cells 1 (NFAT1) is a novel regulator of the Mouse Double Minute 2 (MDM2) oncogene and the NFAT1-MDM2 pathway has been implicated in human cancer development and progression, justifying that targeting the NFAT1-MDM2 pathway could be a novel strategy for discovery and development of novel cancer therapeutics. The present study was designed to examine the anticancer activity and underlying mechanisms of action of lineariifolianoid A (LinA), a novel natural product inhibitor of the NFAT1-MDM2 pathway.

Inulanolide A as a new dual inhibitor of NFAT1-MDM2 pathway for breast cancer therapy.

The transcription factor NFAT1 and the oncogene MDM2 have crucial roles in breast cancer development, progression, and metastasis. We have recently discovered that NFAT1 activates MDM2 expression. Here, we identified a small molecule (named Inulanolide A) that dually inhibited both NFAT1 and MDM2 in breast cancer cells in vitro and in vivo.

Inhibiting NFAT1 for breast cancer therapy: New insights into the mechanism of action of MDM2 inhibitor JapA.

Transcription factor NFAT1 has been recently identified as a new regulator of the MDM2 oncogene. Targeting the NFAT1-MDM2 pathway represents a novel approach to cancer therapy. We have recently identified a natural product MDM2 inhibitor, termed JapA.

RYBP predicts survival of patients with non-small cell lung cancer and regulates tumor cell growth and the response to chemotherapy.

Ring1 and YY1 binding protein (RYBP) is a member of the Polycomb group (PcG) proteins and regulates cell growth through both PcG-dependent and -independent mechanisms. Our initial study indicated that RYBP is down-regulated in human non-small cell lung cancer (NSCLC) tissues. The present study determined the molecular role of RYBP in the development of NSCLC.

Development and validation of an HPLC-MS/MS analytical method for quantitative analysis of TCBA-TPQ, a novel anticancer makaluvamine analog, and application in a pharmacokinetic study in rats.

We have recently designed and synthesized several novel iminoquinone anticancer agents that have entered preclinical development for the treatment of human cancers. Herein we developed and validated a quantitative HPLC-MS/MS analytical method for one of the lead novel anticancer makaluvamine analog, TCBA-TPQ, and conducted a pharmacokinetic study in laboratory rats. Our results indicated that the HPLC-MS/MS method was precise, accurate, and specific.

Polycomb Group (PcG) Proteins and Human Cancers: Multifaceted Functions and Therapeutic Implications.

Polycomb group (PcG) proteins are transcriptional repressors that regulate several crucial developmental and physiological processes in the cell. More recently, they have been found to play important roles in human carcinogenesis and cancer development and progression. The deregulation and dysfunction of PcG proteins often lead to blocking or inappropriate activation of developmental pathways, enhancing cellular proliferation, inhibiting apoptosis, and increasing the cancer stem cell population.

Oral nano-delivery of anticancer ginsenoside 25-OCH3-PPD, a natural inhibitor of the MDM2 oncogene: Nanoparticle preparation, characterization, in vitro and in vivo anti-prostate cancer activity, and mechanisms of action.

The Mouse Double Minute 2 (MDM2) oncogene plays a critical role in cancer development and progression through p53-dependent and p53-independent mechanisms. Both natural and synthetic MDM2 inhibitors have been shown anticancer activity against several human cancers. We have recently identified a novel ginsenoside, 25-OCH3-PPD (GS25), one of the most active anticancer ginsenosides discovered thus far, and have demonstrated its MDM2 inhibition and anticancer activity in various human cancer models, including prostate cancer.

Identification of a new class of natural product MDM2 inhibitor: In vitro and in vivo anti-breast cancer activities and target validation.

The MDM2 oncogene has been suggested as a molecular target for treating human cancers, including breast cancer. Most MDM2 inhibitors under development are targeting the MDM2-p53 binding, and have little or no effects on cancers without functional p53, such as advanced breast cancer. The present study was designed to develop a new class of MDM2 inhibitors that exhibit anticancer activity in MDM2-dependent and p53-independent manners.

RYBP expression is associated with better survival of patients with hepatocellular carcinoma (HCC) and responsiveness to chemotherapy of HCC cells in vitro and in vivo.

RYBP is a member of the polycomb group (PcG) proteins that typically act as transcriptional repressors via epigenetic modification of chromatin. The present study was designed to investigate the role of RYBP in HCC progression, chemosensitivity, and patient survival, and to explore the underlying molecular mechanism(s). In this study we investigated the expression of RYBP in 400 pairs of human HCC tissues and matched noncancerous samples.

Development and validation of a rapid HPLC method for quantitation of SP-141, a novel pyrido[b]indole anticancer agent, and an initial pharmacokinetic study in mice.

There is an increasing interest in targeting the MDM2 oncogene for cancer therapy. SP-141, a novel designed small molecule MDM2 inhibitor, exerts excellent in vitro and in vivo anticancer activity. To facilitate the preclinical development of this candidate anticancer agent, we have developed an HPLC method for the quantitative analysis of SP-141.

The pyrido[b]indole MDM2 inhibitor SP-141 exerts potent therapeutic effects in breast cancer models.

A requirement for Mouse Double Minute 2 (MDM2) oncogene activation has been suggested to be associated with cancer progression and metastasis, including breast cancer. To date, most MDM2 inhibitors have been designed to block the MDM2-p53-binding interphase, and have low or no efficacy against advanced breast cancer with mutant or deficient p53. Here we use a high-throughput screening and computer-aided, structure-based rational drug design, and identify a lead compound, SP-141, which can directly bind to MDM2, inhibit MDM2 expression and induce its autoubiquitination and proteasomal degradation.

Identification of a new class of MDM2 inhibitor that inhibits growth of orthotopic pancreatic tumors in mice.

Background & Aims: The oncogene MDM2, which encodes an E3 ubiquitin ligase, is overexpressed in pancreatic cancers and is therefore a therapeutic target. Current inhibitors of MDM2 target the interaction between MDM2 and P53; these would have no effect on cancer cells that do not express full-length P53, including many pancreatic cancer cells. We searched for a compound that specifically inhibits MDM2 itself.

Selective cytotoxicity, inhibition of cell cycle progression, and induction of apoptosis in human breast cancer cells by sesquiterpenoids from Inula lineariifolia Turcz.

Four new sesquiterpenoid dimers (lineariifolianoids E-H, 1-4), five new sesquiterpenoids (5-9), and seven known sesquiterpenoids (10-16) were isolated from the aerial parts of Inula lineariifolia Turcz. Their structures were determined by spectroscopic data analysis and X-ray diffraction studies. The compounds were then evaluated for their in vitro cytotoxicity against two human breast cancer cell lines (MCF-7 and MDA-MB-231) and one normal breast cell line (MCF-10A).

miRNAs in cancer prevention and treatment and as molecular targets for natural product anticancer agents.

MicroRNAs (miRNAs) are endogenous small non-coding RNAs that regulate gene expression by binding to the 3´untranslated region of target mRNA, resulting in posttranscriptional gene silencing via mRNA degradation or translation inhibition. miRNAs are involved in many biological processes including carcinogenesis. They can act as oncogenes or tumor suppressors and their aberrant expressions are intimately linked with cancer development and progression.

Natural product ginsenoside 25-OCH3-PPD inhibits breast cancer growth and metastasis through down-regulating MDM2.

Although ginseng and related herbs have a long history of utility for various health benefits, their application in cancer therapy and underlying mechanisms of action are not fully understood. Our recent work has shown that 20(S)-25-methoxyl-dammarane-3β, 12β, 20-triol (25-OCH(3)-PPD), a newly identified ginsenoside from Panax notoginseng, exerts activities against a variety of cancer cells in vitro and in vivo. This study was designed to investigate its anti-breast cancer activity and the underlying mechanisms of action.

Preclinical evaluation of anticancer efficacy and pharmacological properties of FBA-TPQ, a novel synthetic makaluvamine analog.

We have recently designed and synthesized a novel iminoquinone anticancer agent, 7-(4-fluorobenzylamino)-1,3,4,8-tetrahydropyrrolo[4,3,2-de]quinolin-8(1H)-one (FBA-TPQ) and initiated its preclinical development. Herein we investigated its efficacy, safety, and pharmacokinetics in in vitro and in vivo models of human pancreatic cancer. Our results demonstrated that FBA-TPQ inhibited pancreatic cancer cell growth, induced apoptosis, and caused cell cycle arrest in vitro.