ATP-competitive inhibitors of the mammalian target of rapamycin: design and synthesis of highly potent and selective pyrazolopyrimidines.
The mammalian target of rapamycin (mTOR), a central regulator of growth, survival, and metabolism, is a validated target for cancer therapy. Rapamycin and its analogues, allosteric inhibitors of mTOR, only partially inhibit one mTOR protein complex. ATP-competitive, global inhibitors of mTOR that have the potential for enhanced anticancer efficacy are described. Structural features leading to potency and selectivity were identified and refined leading to compounds with in vivo efficacy in tumor xenograft models.
Zask
Arie
A
Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, USA. zaska@wyeth.com
Verheijen
Jeroen C
JC
Curran
Kevin
K
Kaplan
Joshua
J
Richard
David J
DJ
Nowak
Pawel
P
Malwitz
David J
DJ
Brooijmans
Natasja
N
Bard
Joel
J
Svenson
Kristine
K
Lucas
Judy
J
Toral-Barza
Lourdes
L
Zhang
Wei-Guo
WG
Hollander
Irwin
I
Gibbons
James J
JJ
Abraham
Robert T
RT
Ayral-Kaloustian
Semiramis
S
Mansour
Tarek S
TS
Yu
Ker
K
D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D058544:Class Ib Phosphatidylinositol 3-Kinase; D018360:Crystallography, X-Ray; D015195:Drug Design; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D007527:Isoenzymes / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D008861:Microsomes / Q000378:metabolism; D008958:Models, Molecular; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases; D014508:Urea / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D000255:Adenosine Triphosphate; D000970:Antineoplastic Agents; D002219:Carbamates; D058544:Class Ib Phosphatidylinositol 3-Kinase; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011720:Pyrazoles; D011743:Pyrimidines; D058570:TOR Serine-Threonine Kinases; D014508:Urea; C546843:mTOR protein, mouse; C546764:Pik3cg protein, mouse