Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition.
We have designed MI-219 as a potent, highly selective and orally active small-molecule inhibitor of the MDM2-p53 interaction. MI-219 binds to human MDM2 with a K(i) value of 5 nM and is 10,000-fold selective for MDM2 over MDMX. It disrupts the MDM2-p53 interaction and activates the p53 pathway in cells with wild-type p53, which leads to induction of cell cycle arrest in all cells and selective apoptosis in tumor cells. MI-219 stimulates rapid but transient p53 activation in established tumor xenograft tissues, resulting in inhibition of cell proliferation, induction of apoptosis, and complete tumor growth inhibition. MI-219 activates p53 in normal tissues with minimal p53 accumulation and is not toxic to animals. MI-219 warrants clinical investigation as a new agent for cancer treatment.
Shangary
Sanjeev
S
Comprehensive Cancer Center and Department of Internal Medicine, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA.
Qin
Dongguang
D
McEachern
Donna
D
Liu
Meilan
M
Miller
Rebecca S
RS
Qiu
Su
S
Nikolovska-Coleska
Zaneta
Z
Ding
Ke
K
Wang
Guoping
G
Chen
Jianyong
J
Bernard
Denzil
D
Zhang
Jian
J
Lu
Yipin
Y
Gu
Qingyang
Q
Shah
Rajal B
RB
Pienta
Kenneth J
KJ
Ling
Xiaolan
X
Kang
Sanmao
S
Guo
Ming
M
Sun
Yi
Y
Yang
Dajun
D
Wang
Shaomeng
S
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular; D009369:Neoplasms / Q000473:pathology*; D011485:Protein Binding / Q000187:drug effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D013141:Spiro Compounds / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D007211:Indoles; C574930:MI-219; D013141:Spiro Compounds; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2