Antitumor activity of SCH 66336, an orally bioavailable tricyclic inhibitor of farnesyl protein transferase, in human tumor xenograft models and wap-ras transgenic mice.
We have been developing a series of nonpeptidic, small molecule farnesyl protein transferase inhibitors that share a common tricyclic nucleus and compete with peptide/protein substrates for binding to farnesyl protein transferase. Here, we report on pharmacological and in vivo studies with SCH 66336, a lead compound in this structural class. SCH 66336 potently inhibits Ha-Ras processing in whole cells and blocks the transformed growth properties of fibroblasts and human tumor cell lines expressing activated Ki-Ras proteins. The anchorage-independent growth of many human tumor lines that lack an activated ras oncogene is also blocked by treatment with SCH 66336. In mouse, rat, and monkey systems, SCH 66336 has excellent oral bioavailability and pharmacokinetic properties. In the nude mouse, SCH 66336 demonstrated potent oral activity in a wide array of human tumor xenograft models including tumors of colon, lung, pancreas, prostate, and urinary bladder origin. Enhanced in vivo efficacy was observed when SCH 66336 was combined with various cytotoxic agents (cyclophosphamide, 5-fluorouracil, and vincristine). In a Ha-Ras transgenic mouse model, prophylactic treatment with SCH 66336 delayed tumor onset, reduced the average number of tumors/mouse, and reduced the average tumor weight/animal. In a therapeutic mode in which gavage treatment was initiated after the transgenic mice had developed palpable tumors, significant tumor regression was induced by SCH 66336 in a dose-dependent fashion. This was associated with increased apoptosis and decreased DNA synthesis in tumors of animals treated with SCH 66336. Enhanced efficacy was also observed in this model when SCH 66336 was combined with cyclophosphamide. SCH 66336 is presently being evaluated in Phase I clinical trials.
Liu
M
M
Department of Biological Research-Oncology, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA.
Bryant
M S
MS
Chen
J
J
Lee
S
S
Yaremko
B
B
Lipari
P
P
Malkowski
M
M
Ferrari
E
E
Nielsen
L
L
Prioli
N
N
Dell
J
J
Sinha
D
D
Syed
J
J
Korfmacher
W A
WA
Nomeir
A A
AA
Lin
C C
CC
Wang
L
L
Taveras
A G
AG
Doll
R J
RJ
Njoroge
F G
FG
Mallams
A K
AK
Remiszewski
S
S
Catino
J J
JJ
Girijavallabhan
V M
VM
Bishop
W R
WR
D016475:3T3 Cells; D000284:Administration, Oral; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001973:Bromodeoxyuridine / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D011905:Genes, ras / Q000502:physiology*; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D010880:Piperidines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D014183:Transplantation, Heterologous; D003986:Dibenzocycloheptenes
D019883:Alkyl and Aryl Transferases; D000970:Antineoplastic Agents; D001973:Bromodeoxyuridine; D004791:Enzyme Inhibitors; D010880:Piperidines; D011725:Pyridines; C064911:p21(ras) farnesyl-protein transferase; C115354:lonafarnib; D003986:Dibenzocycloheptenes