Photo‐Cross‐Linked Small‐Molecule Affinity Matrix for Facilitating Forward and Reverse Chemical Genetics

Kanoh, Naoki; Honda, Kaori; Simizu, Siro; Muroi, Makoto; Osada, Hiroyuki

doi:10.1002/anie.200462370

Cited by 110 publications

(57 citation statements)

References 19 publications

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“…To identify the disulfide bond arrangements within heparanase, we did a matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass analysis with a slight modification (34)(35)(36). To determine the disulfide bond between Cys 437 and Cys 542 , after electrophoresis under nonreducing condition, the protein-containing area was excised, washed, and then dried under reduced pressure.…”

Section: Methodsmentioning

confidence: 99%

Involvement of Disulfide Bond Formation in the Activation of Heparanase

Simizu¹,

Suzuki

Muroi³

et al. 2007

Cancer Research

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Heparanase is overexpressed in many solid tumor cells and is capable of specifically cleaving heparan sulfate, and this activity is associated with the metastatic potential of tumor cells; however, the activation mechanism of heparanase has remained unknown. In this study, we investigated the link between disulfide bond formation and the activation of heparanase in human tumor cells. Mass spectrometry analysis of heparanase purified from a conditioned medium of human fibrosarcoma cells revealed two disulfide bonds, Cys

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Section: Methodsmentioning

confidence: 99%

Involvement of Disulfide Bond Formation in the Activation of Heparanase

Simizu¹,

Suzuki

Muroi³

et al. 2007

Cancer Research

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“…After reduction and alkylation of the samples, in-gel digestion was performed with trypsin or Achromobacter protease I. The resulting peptides were extracted and analyzed by MALDI-TOF MS (16). The protein was identified from peptide mass fingerprinting by using the Mascot search program and the Swiss-Prot database.…”

Section: Detection Of Binding Proteins For M-gfn Beadsmentioning

confidence: 99%

“…In this method, aryldiazirine groups covalently attached to solid supports are transformed upon UV irradiation into highly reactive carbenes, which are expected to bind to or insert irreversibly into proximal small molecules in a functional group-independent manner. We have applied this method to construct small-molecule microarrays (14,15) and small-molecule affinity matrices (16).…”

mentioning

confidence: 99%

The identification of an osteoclastogenesis inhibitor through the inhibition of glyoxalase I

Kawatani

Okumura

Honda

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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105

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Osteoclasts, bone-resorptive multinucleated cells derived from hematopoietic stem cells, are associated with many bone-related diseases, such as osteoporosis. Osteoclast-targeting small-molecule inhibitors are valuable tools for studying osteoclast biology and for developing antiresorptive agents. Here, we have discovered that methyl-gerfelin (M-GFN), the methyl ester of the natural product gerfelin, suppresses osteoclastogenesis. By using M-GFNimmobilized beads, glyoxalase I (GLO1) was identified as an M-GFN-binding protein. GLO1 knockdown and treatment with an established GLO1 inhibitor in osteoclast progenitor cells interfered with osteoclast generation, suggesting that GLO1 activity is required for osteoclastogenesis. In cells, GLO1 plays a critical role in the detoxification of 2-oxoaldehydes, such as methylglyoxal. M-GFN inhibited the enzymatic activity of GLO1 in vitro and in situ. Furthermore, the cocrystal structure of the GLO1/M-GFN complex revealed the binding mode of M-GFN at the active site of GLO1. These results suggest that M-GFN targets GLO1, resulting in the inhibition of osteoclastogenesis.osteoclast ͉ small molecule ͉ crystal structure

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“…4a). (51)(52)(53) This photocross-linking method is a coupling technique that enables the introduction of a variety of small molecules onto solid supports through a photoaffinity reaction. In this method, aryldiazirine groups covalently attach to solid supports and are transformed by ultraviolet (UV) irradiation into highly reactive carbenes, which bind to or irreversibly insert into proximal small molecules in a functional group-independent manner.…”

Section: Small Molecules That Selectively Inhibit Osteoclast Functionmentioning

confidence: 99%

Osteoclast‐targeting small molecules for the treatment of neoplastic bone metastases

Kawatani

Osada

2009

Cancer Science

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Osteoclasts are highly specialized cells that resorb bone, and their abnormal activity is implicated in a variety of human bone diseases. In neoplastic bone metastasis, the bone destruction caused by osteoclasts is not only associated with the formation and progression of metastatic lesions, but also could contribute to frequent complications such as severe pain and pathological fractures, which greatly diminish the quality of life of patients. Bisphosphonates, potent antiresorptive drugs, have been shown to have efficacy for treating bone metastases in many types of cancer, and the development of various molecularly targeted agents is currently proceeding. Thus, inhibition of osteoclast function is now established as an important treatment strategy for bony metastases. This review focuses on promising small molecules that disrupt osteoclast function and introduces our chemical ⁄ biological approach for identifying osteoclast-targeting small molecular inhibitors. (Cancer Sci 2009; 100: 1999 B one is a dynamic organ that constantly repeats the cycle of formation by osteoblasts and destruction (resorption) by osteoclasts throughout life.(1) Bone remodeling is necessary for skeletal growth and to maintain normal bone tissue. Imbalances of remodeling can result in gross perturbations in skeletal structure and function, potentially causing morbidity. Most adult skeletal diseases are due to excess osteoclastic bone resorption, including osteoporosis, rheumatoid arthritis, and neoplastic bone metastasis.(2) Bone, as well as lung and liver, is one of the most preferential metastatic sites for common human malignancies, notably breast, prostate, and lung cancers.(3) Bone metastases are frequently associated with severe bone pain, pathological fractures, hypercalcemia, and spinal cord compression syndromes that greatly diminish the quality of life for patients. Although bone metastases are histopathologically classified as osteolytic, osteoblastic, or mixed lesions, accumulating evidence suggests that bone resorption by osteoclasts plays a pivotal role in the development and progression of all types of metastasis.(4) In fact, bone-residing metastatic cells are not directly able to destroy the hard bone tissue to enable them to survive and grow within bone. Instead, they secrete paracrine factors, such as parathyroid hormone-related peptide (PTHrP) and interleukin-6 (IL-6), which directly or indirectly stimulate osteoclast differentiation and activation. In turn, bone resorption by osteoclasts releases growth factors such as transforming growth factor-b (TGF-b) and insulin-like growth factor-1 (IGF-1) from the bone matrix that promote tumor growth. This interaction between tumor cells and the bony microenvironment results in a vicious cycle of bone destruction and tumor growth (Fig. 1).(4) Furthermore, excessive osteoclastic bone destruction could be a factor that causes the complications of metastases.The concept of the vicious cycle alters the approach to the treatment of bone metastases, because it means that antiresorp...

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Photo‐Cross‐Linked Small‐Molecule Affinity Matrix for Facilitating Forward and Reverse Chemical Genetics

Abstract: In this communication, the structure of activated CH agarose 4B beads (2), which were purchased from Amersham Bioscience, and the following structures (3 and 4) in Scheme 1 were rendered incorrectly; the correct structures are shown. The authors apologize for this oversight.

Cited by 110 publications

References 19 publications

Involvement of Disulfide Bond Formation in the Activation of Heparanase

Involvement of Disulfide Bond Formation in the Activation of Heparanase

The identification of an osteoclastogenesis inhibitor through the inhibition of glyoxalase I

Osteoclast‐targeting small molecules for the treatment of neoplastic bone metastases

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