Discovery of a fluoroindolo[2,3-a]carbazole clinical candidate with broad spectrum antitumor activity in preclinical tumor models superior to the marketed oncology drug, CPT-11.
A series of fluoroglycosylated fluoroindolocarbazoles was examined with respect to their topoisomerase I activity, cytotoxicity, and selectivity. The lead clinical candidate from this series, BMS-250749, displays broad spectrum antitumor activity superior to CPT-11 against some preclinical xenograft models, including curative antitumor activity against Lewis lung carcinoma.
Saulnier
Mark G
MG
The Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, Connecticut 06492, USA. Mark.Saulnier@bms.com
Balasubramanian
Balu N
BN
Long
Byron H
BH
Frennesson
David B
DB
Ruediger
Edward
E
Zimmermann
Kurt
K
Eummer
Jeffrey T
JT
St Laurent
Denis R
DR
Stoffan
Karen M
KM
Naidu
B Narasimhulu
BN
Mahler
Mikael
M
Beaulieu
Francis
F
Bachand
Carol
C
Lee
Frank Y
FY
Fairchild
Craig R
CR
Stadnick
Linda K
LK
Rose
William C
WC
Solomon
Carola
C
Wong
Henry
H
Martel
Alain
A
Wright
John J
JJ
Kramer
Robert
R
Langley
David R
DR
Vyas
Dolatrai M
DM
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002227:Carbazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005960:Glucosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000077146:Irinotecan; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D059004:Topoisomerase I Inhibitors; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; C500156:BMS 250749; D002227:Carbazoles; D005960:Glucosides; D007211:Indoles; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D002166:Camptothecin