2-Anilino-4-aryl-1,3-thiazole inhibitors of valosin-containing protein (VCP or p97).
Valosin-containing protein (VCP; also known as p97) is a member of the AAA ATPase family with a central role in the ubiquitin-degradation of misfolded proteins. VCP also exhibits antiapoptotic function and metastasis via activation of nuclear factor kappa-B signaling pathway. We have discovered that 2-anilino-4-aryl-1,3-thiazoles are potent drug-like inhibitors of this enzyme. The identified compounds show low nanomolar VCP potency, demonstrate SAR trends, and show activity in a mechanism based cellular assay. This series of compounds represents the first steps towards a novel, small molecule VCP inhibitor as a cancer therapeutic.
Bursavich
Matthew G
MG
Medicinal Chemistry, Myriad Pharmaceuticals, Inc., 305 South Chipeta Way, Salt Lake City, UT 84108, United States. Matthew.Bursavich@myriadpharma.com
Parker
Daniel P
DP
Willardsen
J Adam
JA
Gao
Zhong-Hua
ZH
Davis
Thaylon
T
Ostanin
Kirill
K
Robinson
Rosann
R
Peterson
Ashley
A
Cimbora
Daniel M
DM
Zhu
Ju-Fen
JF
Richards
Burt
B
D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000814:Aniline Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000074405:Valosin Containing Protein
D000814:Aniline Compounds; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D016328:NF-kappa B; D013844:Thiazoles; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein