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Author

Cornelis P. Vlaar

Other affiliations: University of Puerto Rico
Bio: Cornelis P. Vlaar is an academic researcher from University of Puerto Rico, Medical Sciences Campus. The author has contributed to research in topics: Metastasis & Cancer. The author has an hindex of 6, co-authored 16 publications receiving 376 citations. Previous affiliations of Cornelis P. Vlaar include University of Puerto Rico.

Papers
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Journal ArticleDOI
TL;DR: It is demonstrated that EHop-016 inhibits Rac activity in the MDA-MB-435 metastatic cancer cells that overexpress Rac and exhibits high endogenous Rac activity, and holds promise as a targeted therapeutic agent for the treatment of metastatic cancers with high Rac activity.

192 citations

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TL;DR: EHop-016 has potential as an anticancer compound to block cancer progression via multiple Rac-directed mechanisms and affected cell viability by down-regulating Akt and Jun kinase activities and c-Myc and Cyclin D expression, as well as increasing caspase 3/7 activities in metastatic cancer cells.

65 citations

Journal ArticleDOI
TL;DR: MBQ-167 is 10× more potent than other currently available Rac/Cdc42 inhibitors and has the potential to be developed as an anticancer drug, as well as a dual inhibitory probe for the study of Rac and Cdc42.
Abstract: The Rho GTPases Rac (Ras-related C3 botulinum toxin substrate) and Cdc42 (cell division control protein 42 homolog) regulate cell functions governing cancer malignancy, including cell polarity, migration, and cell-cycle progression. Accordingly, our recently developed Rac inhibitor EHop-016 (IC50, 1,100 nmol/L) inhibits cancer cell migration and viability and reduces tumor growth, metastasis, and angiogenesis in vivo Herein, we describe MBQ-167, which inhibits Rac and Cdc42 with IC50 values of 103 and 78 nmol/L, respectively, in metastatic breast cancer cells. Consequently, MBQ-167 significantly decreases Rac and Cdc42 downstream effector p21-activated kinase (PAK) signaling and the activity of STAT3, without affecting Rho, MAPK, or Akt activities. MBQ-167 also inhibits breast cancer cell migration, viability, and mammosphere formation. Moreover, MBQ-167 affects cancer cells that have undergone epithelial-to-mesenchymal transition by a loss of cell polarity and inhibition of cell surface actin-based extensions to ultimately result in detachment from the substratum. Prolonged incubation (120 hours) in MBQ-167 decreases metastatic cancer cell viability with a GI50 of approximately 130 nmol/L, without affecting noncancer mammary epithelial cells. The loss in cancer cell viability is due to MBQ-167-mediated G2-M cell-cycle arrest and subsequent apoptosis, especially of the detached cells. In vivo, MBQ-167 inhibits mammary tumor growth and metastasis in immunocompromised mice by approximately 90%. In conclusion, MBQ-167 is 10× more potent than other currently available Rac/Cdc42 inhibitors and has the potential to be developed as an anticancer drug, as well as a dual inhibitory probe for the study of Rac and Cdc42. Mol Cancer Ther; 16(5); 805-18. ©2017 AACR.

62 citations

Journal ArticleDOI
TL;DR: A simple two-step procedure for the conversion of readily available phthalides to the corresponding benzoxazinones was developed and conveniently provided a variety of 4-substituted benzoxzinones.

45 citations

Journal ArticleDOI
TL;DR: Pak and Rac GTPases, including Vav1, are identified as potential therapeutic targets in MPN and AML involving an oncogenic form of KIT.
Abstract: An acquired somatic mutation at codon 816 in the KIT receptor tyrosine kinase is associated with poor prognosis in patients with systemic mastocytosis and acute myeloid leukemia (AML). Treatment of leukemic cells bearing this mutation with an allosteric inhibitor of p21–activated kinase (Pak) or its genetic inactivation results in growth repression due to enhanced apoptosis. Inhibition of the upstream effector Rac abrogates the oncogene-induced growth and activity of Pak. Although both Rac1 and Rac2 are constitutively activated via the guanine nucleotide exchange factor (GEF) Vav1, loss of Rac1 or Rac2 alone moderately corrected the growth of KIT-bearing leukemic cells, whereas the combined loss resulted in 75% growth repression. In vivo, the inhibition of Vav or Rac or Pak delayed the onset of myeloproliferative neoplasms (MPNs) and corrected the associated pathology in mice. To assess the role of Rac GEFs in oncogene-induced transformation, we used an inhibitor of Rac, EHop-016, which specifically targets Vav1 and found that EHop-016 was a potent inhibitor of human and murine leukemic cell growth. These studies identify Pak and Rac GTPases, including Vav1, as potential therapeutic targets in MPN and AML involving an oncogenic form of KIT.

41 citations


Cited by
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Journal ArticleDOI
TL;DR: One of the goals of this Review is to attract the attention of the scientific community as to the benefits of using hypervalent iodine compounds as an environmentally sustainable alternative to heavy metals.
Abstract: The preparation, structure, and chemistry of hypervalent iodine compounds are reviewed with emphasis on their synthetic application. Compounds of iodine possess reactivity similar to that of transition metals, but have the advantage of environmental sustainability and efficient utilization of natural resources. These compounds are widely used in organic synthesis as selective oxidants and environmentally friendly reagents. Synthetic uses of hypervalent iodine reagents in halogenation reactions, various oxidations, rearrangements, aminations, C–C bond-forming reactions, and transition metal-catalyzed reactions are summarized and discussed. Recent discovery of hypervalent catalytic systems and recyclable reagents, and the development of new enantioselective reactions using chiral hypervalent iodine compounds represent a particularly important achievement in the field of hypervalent iodine chemistry. One of the goals of this Review is to attract the attention of the scientific community as to the benefits of...

1,228 citations

Journal ArticleDOI
TL;DR: Three PI3K-dependent, but AKT-independent, signaling branches that have recently been shown to have important roles in promoting phenotypes associated with malignancy are highlighted.

330 citations

Journal ArticleDOI
TL;DR: In this paper, the authors present Phthalides A 1.1.1, a 1.5-approximation of the original Phthalide A 1, which they call
Abstract: 1. Phthalides A 1.

262 citations

Journal ArticleDOI
TL;DR: This review emphasizes the recent advances in 1,2,3-triazole-containing hybrids with anticancer potential, covering articles published between 2015 and 2019, and the structure-activity relationships, together with mechanisms of action are discussed.

253 citations

Journal ArticleDOI
TL;DR: In this article, the authors focus on one master regulator of cell motility, RAC1, and the existing data with regard to its role in cell motability, including particular roles for tumor angiogenesis and invasion/metastasis.
Abstract: Angiogenesis and metastasis are well recognized as processes fundamental to the development of malignancy. Both processes involve the coordination of multiple cellular and chemical activities through myriad signaling networks, providing a mass of potential targets for therapeutic intervention. This review will focus on one master regulator of cell motility, RAC1, and the existing data with regard to its role in cell motility, including particular roles for tumor angiogenesis and invasion/metastasis. We also emphasize the preclinical investigations carried out with RAC1 inhibitors to evaluate the therapeutic potential of this target. Herein, we explore potential future directions as well as the challenges of targeting RAC1 in the treatment of cancer. Recent insights at the molecular and cellular levels are paving the way for a more directed and detailed approach to target mechanisms of RAC1 regulating angiogenesis and metastasis. Understanding these mechanisms may provide insight into RAC1 signaling components as alternative therapeutic targets for tumor angiogenesis and metastasis.

223 citations