Dianqing Q Wu

US Patent:

8461155, Jun 11, 2013

Filed:

Mar 18, 2005

Appl. No.:

11/084668

Inventors:

Dianqing (Dan) Wu - Cheshire CT, US
Xiaofeng Li - West Hartford CT, US

Assignee:

University of Connecticut - Farmington CT

International Classification:

A61K 31/535
C07C 50/18

US Classification:

5142298, 552208

Abstract:

The loss of the SOST gene product sclerostin leads to sclerosteosis characterized by high bone mass (HBM). In this report, we found that sclerostin could antagonize canonical Wnt signaling in human embryonic kidney A293 cells and mouse osteoblastic MC3T3 cells. This sclerostin-mediated antagonism could be reversed by over-expression of Wnt coreceptor LRP5. In addition, we found that sclerostin bound to LRP5 as well as LRP6 and identified the first two YWTD-EGF repeat domains of LRP5 as being responsible for the binding. Although these two repeat domains are required for transducing canonical Wnt signals, canonical Wnt did not appear to compete with sclerostin for binding to LRP5. Examination of the expression of sclerostin and Wnt7b, an autocrine canonical Wnt, during primary calvarial osteoblast differentiation revealed that sclerostin is expressed at the late stages of osteoblast differentiation coinciding with the expression of osteogenic marker osteocalcin and trailing after the expression of Wnt7b. Given the plethora of evidence indicating that canonical Wnt signaling stimulates osteogenesis, we believe that the HBM phenotype associated with the loss of sclerostin may at least in part be attributed to an increase in canonical Wnt signaling resulting from the reduction in sclerostin-mediated Wnt antagonism.

US Patent:

20080119402, May 22, 2008

Filed:

Apr 1, 2005

Appl. No.:

11/097518

Inventors:

Jie Zheng - Memphis TN, US
Jufang Shan - Memphis TN, US
Dianqing Wu - Cheshire CT, US

International Classification:

A61K 31/16
A61K 31/165
A61K 31/195
A61K 31/20
A61K 31/235
A61K 31/351
A61K 31/381
A61K 31/4025
A61K 31/41
A61K 31/415
A61K 31/50
A61K 31/505
A61K 31/519
A61K 31/53
A61K 31/5377
A61K 31/70
A61K 38/02
A61K 38/16
A61P 3/00
A61P 35/00
A61P 5/00
C40B 20/08
C40B 30/02
C40B 30/04

US Classification:

514 12, 506 6, 506 8, 506 9, 514183, 514 2, 514 23, 5142362, 514245, 514248, 514249, 5142621, 514274, 514383, 514404, 514422, 514444, 514447, 514460, 514533, 514558, 514563, 514568, 514614, 514619, 514789

Abstract:

The Wnt signaling pathways are involved in embryo development as well as in tumorigenesis. Dishevelled (Dvl) tranduces Wnt signals from the receptor Frizzled (Fz) to downstream components in canonical and non-canonical Wnt signaling pathways, and the Dvl PDZ domain plays an essential role in both pathways, and the Dvl PDZ domain binds directly to Fz receptors. In the present invention using NMR-assisted virtual ligand screening, several compounds were identified and were found to bind to the Dvl PDZ domain. Molecular dynamics simulation was used to analyze the binding between the PDZ domain and these compounds in detail. These compounds provide a basis for rational design of high-affinity inhibitors of the PDZ domain, which can block Wnt signaling by interrupting the Fz-Dvl interaction.

US Patent:

20100074891, Mar 25, 2010

Filed:

Oct 2, 2009

Appl. No.:

12/587205

Inventors:

Dianqing Dan Wu - Cheshire CT, US
Xiaofeng Li - West Hartford CT, US

International Classification:

A61K 39/395
A61K 38/02
A61K 38/14
A61K 38/16
A61K 31/70
A61K 31/20
A61P 35/00

US Classification:

4241301, 514 2, 514 12, 514 8, 514 23, 514558

Abstract:

The loss of the SOST gene product sclerostin leads to sclerosteosis characterized by high bone mass (HBM). In this report, we found that sclerostin could antagonize canonical Wnt signaling in human embryonic kidney A293 cells and mouse osteoblastic MC3T3 cells. This sclerostin-mediated antagonism could be reversed by over-expression of Wnt coreceptor LRP5. In addition, we found that sclerostin bound to LRP5 as well as LRP6 and identified the first two YWTD-EGF repeat domains of LRP5 as being responsible for the binding. Although these two repeat domains are required for transducing canonical Wnt signals, canonical Wnt did not appear to compete with sclerostin for binding to LRP5. Examination of the expression of sclerostin and Wnt7b, an autocrine canonical Wnt, during primary calvarial osteoblast differentiation revealed that sclerostin is expressed at the late stages of osteoblast differentiation coinciding with the expression of osteogenic marker osteocalcin and trailing after the expression of Wnt7b. Given the plethora of evidence indicating that canonical Wnt signaling stimulates osteogenesis, we believe that the HBM phenotype associated with the loss of sclerostin may at least in part be attributed to an increase in canonical Wnt signaling resulting from the reduction in sclerostin-mediated Wnt antagonism.

US Patent:

20100298308, Nov 25, 2010

Filed:

Nov 14, 2006

Appl. No.:

11/598916

Inventors:

Dianqing (Dan) Wu - Cheshire CT, US
Dakai Liu - South Setauket NY, US
James J. Donegan - Long Beach NY, US

International Classification:

A61K 31/538
G01N 33/566
C40B 30/02
A61K 31/185
A61K 31/18
A61K 31/166
C07D 265/34
C07D 265/38
C07D 213/56
C07C 309/32
C07C 309/89
C07C 311/16
C07C 311/21
C07C 233/40
A61P 3/00
A61P 3/08
A61P 3/06
A61P 35/00
A61P 19/08
A61P 3/10
A61P 25/00

US Classification:

5142298, 436501, 506 8, 5142295, 514576, 514577, 514603, 514604, 514622, 544 99, 544102, 546316, 562 47, 562826, 564 86, 564 92, 564158

Abstract:

The mechanism by which the high bone mass (HBM) mutation (G171V) of the Wnt coreceptor LRP5 regulates the canonical Wnt signaling was investigated. The mutation was previously shown to reduce Dkk protein-1-mediated antagonism, suggesting that the first YWTD repeat domain where G171 is located may be responsible for Dkk protein-mediated antagonism. However, we found that the third YWTD repeat, but not the first repeat domain, is required for DKK1-mediated antagonism. Instead, we found that the G171V mutation disrupted the interaction of LRP5 with Mesd, a chaperon protein for LRP5/6 that is required for the coreceptors' transport to cell surfaces, resulting in less LRP5 molecules on the cell surface. Although the reduction in the level of cell surface LRP5 molecules led to a reduction in Wnt signaling in a paracrine paradigm, the mutation did not appear to affect the activity of coexpressed Wnt in an autocrine paradigm. Together with the observation that osteoblast cells produce autocrine canonical Wnt, Wnt7b, and that osteocytes produce paracrine Dkk1, we believe that the G171V mutation may cause an increase in Wnt activity in osteoblasts by reducing the number of targets for paracrine Dkk1 to antagonize without affecting the activity of autocrine Wnt.

US Patent:

20110086021, Apr 14, 2011

Filed:

Sep 29, 2010

Appl. No.:

12/924560

Inventors:

Dianqing (Dan) Wu - Cheshire CT, US
Xiaofeng Li - West hartford CT, US

Assignee:

ENZO THERAPEUTICS, INC., C/O ENZO BIOCHEM, INC. - NEW YORK NY

International Classification:

A61K 39/395
A61K 38/00
A61K 31/7088
A61K 31/70
A61P 19/00

US Classification:

4241301, 514 167, 514 44 R, 514 23, 514 11

Abstract:

The loss of the SOST gene product sclerostin leads to sclerosteosis characterized by high bone mass (HBM). In this report, we found that sclerostin could antagonize canonical Wnt signaling in human embryonic kidney A293 cells and mouse osteoblastic MC3T3 cells. This sclerostin-mediated antagonism could be reversed by over-expression of Wnt coreceptor LRP5. In addition, we found that sclerostin bound to LRP5 as well as LRP6 and identified the first two YWTD-EGF repeat domains of LRP5 as being responsible for the binding. Although these two repeat domains are required for transducing canonical Wnt signals, canonical Wnt did not appear to compete with sclerostin for binding to LRP5. Examination of the expression of sclerostin and Wnt7b, an autocrine canonical Wnt, during primary calvarial osteoblast differentiation revealed that sclerostin is expressed at the late stages of osteoblast differentiation coinciding with the expression of osteogenic marker osteocalcin and trailing after the expression of Wnt7b. Given the plethora of evidence indicating that canonical Wnt signaling stimulates osteogenesis, we believe that the HBM phenotype associated with the loss of sclerostin may at least in part be attributed to an increase in canonical Wnt signaling resulting from the reduction in sclerostin-mediated Wnt antagonism.