MEK1 inhibitors(Dual specificity mitogen-activated protein kinase kinase 1 inhibitors), MKK4 inhibitors(mitogen-activated protein kinase kinase 4 inhibitors), MKK7 inhibitors(mitogen-activated protein kinase kinase 7 inhibitors)

Therapeutic Areas

NeoplasmsInfectious DiseasesOther Diseases

Active Indication-

Inactive Indication

InflammationMycosesNeoplasms

Originator Organization

Hanwha Corp.

Active Organization

Yonsei University

Inactive Organization

Hanwha Corp.

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

100 Clinical Results associated with HWY-336

100 Translational Medicine associated with HWY-336

100 Patents (Medical) associated with HWY-336

Literatures (Medical) associated with HWY-336

01 Apr 2002·Journal of Biological ChemistryQ2 · BIOLOGY

Selective Inhibition of MAPKK Wis1 in the Stress-activated MAPK Cascade of Schizosaccharomyces pombe by Novel Berberine Derivatives

Q2 · BIOLOGY

Article

Author: Myoung Jin Jang ; Kiwon Song ; Miri Jwa ; Jung Ho Kim

Intracellular molecular targets of novel berberine derivatives, HWY 289 and HWY 336, were identified by a screen of a variety of mutants in fission yeast Schizosaccharomyces pombe. HWY 289 and HWY 336 completely inhibited the proliferation of wild type as well as various mutant fission yeast cells (minimal inhibitory concentrations were 29.52 microm for HWY 289 and 11.83 microm for HWY 336), but did not affect the proliferation of Wis1 mitogen-activated protein kinase kinase (MAPKK) deletion mutants. In addition, HWY 289 with an IC(50) value of 7.3 microm or HWY 336 with IC(50) of 5.7 microm specifically inhibited in vitro kinase activities of purified Wis1, whereas either compound did not affect the activities of other kinases in the mitogen-activated protein kinase (MAPK) cascades of fission yeast. These genetic and biochemical results demonstrate the high degree of specificity of HWY 289 and HWY 336 to MAPKK Wis1 and suggest that the cytotoxicity of these compounds is not simply due to the inhibition of Wis1 kinase activity. High salt wash experiments have shown that strong noncovalent binding occurs between Wis1 and either HWY 289 or HWY 336. The preincubation of Wis1 kinase with ATP did not affect the inhibition of Wis1 by HWY 289 and HWY 336, but when Wis1 was preincubated with MBP, a protein substrate, Wis1 kinase activity was no longer inhibited. These observations demonstrate that HWY 289/HWY 336 do inhibit Wis1 kinase, not by binding to the ATP-binding site but by disturbing the binding of substrate to the kinase. Target validation of the complex of HWY 289/HWY 336 and Wis1 kinase will provide important clues for the mechanism of specific cytotoxicity of these compounds in S. pombe. On a broader aspect, it would create an initiative to further modify and develop compounds that selectively inhibit kinases and cause cytotoxicity in various MAPK cascades including those of mammals.

PLoS ONEQ3 · CROSS-FIELD

A Protoberberine Derivative HWY336 Selectively Inhibits MKK4 and MKK7 in Mammalian Cells: The Importance of Activation Loop on Selectivity

Q3 · CROSS-FIELD

ArticleOA

Author: Gadhe, Changdev G ; Kim, Donghyun ; Cho, Seung Joo ; Oh, Youngjin ; Song, Kiwon ; Kim, Namil ; Park, Jeongyeon

A protoberberine derivative library was used to search for selective inhibitors against kinases of the mitogen-activated protein kinase (MAPK) cascades in mammalian cells. Among kinases in mammalian MAPK pathways, we identified a compound (HWY336) that selectively inhibits kinase activity of mitogen-activated protein kinase kinase 4 and 7 (MKK4 and MKK7). The IC50 of HWY336 was 6 µM for MKK4 and 10 µM for MKK7 in vitro. HWY336 bound to both kinases reversibly via noncovalent interactions, and inhibited their activity by interfering with access of a protein substrate to its binding site. The binding affinity of HWY336 to MKK4 was measured by surface plasmon resonance to determine a dissociation constant (Kd) of 3.2 µM. When mammalian cells were treated with HWY336, MKK4 and MKK7 were selectively inhibited, resulting in inhibition of c-Jun NH2-terminal protein kinases in vivo. The structural model of HWY336 bound to either MKK4 or MKK7 predicted that HWY336 was docked to the activation loop, which is adjacent to the substrate binding site. This model suggested the importance of the activation loop of MKKs in HWY336 selectivity. We verified this model by mutating three critical residues within this loop of MKK4 to the corresponding residues in MKK3. The mutant MKK4 displayed similar kinase activity as wild-type kinase, but its activity was not inhibited by HWY336 compared to wild-type MKK4. We propose that the specific association of HWY336 to the activation loop of MKK4/MKK7 is responsible for its selective inhibition.

100 Deals associated with HWY-336

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Phase 3	KR	Hanwha Corp.	-
Inflammation	Discovery	KR	Hanwha Corp.	-
Mycoses	Discovery	KR	Hanwha Corp.	-

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