| Target Validation Information | |||||
|---|---|---|---|---|---|
| Target ID | T03755 | ||||
| Target Name | Bcl-2-like protein 2 | ||||
| Target Type | Clinical Trial |
||||
| Drug Potency against Target | ABT-263 | Drug Info | Ki < 1 nM | [552892] | |
| Action against Disease Model | ABT-263 | ABT-263 was active against approximately one-half of the cell lines of the PPTP in vitro panel. The median IC(50) for all of the lines in the panel was 1.91 microM. ABT-263 induced significant prolongation of the EFS distribution in 9 of 35 (26%) of the solid t uMor xenografts, and in 5 of 6 (83%) of the evaluable ALL xenografts. ABT-263 induced no objective responses in thesolid t uMor panels, but induced CRs in 3 of 6 evaluable xenografts in the ALL panel, including two that were maintained for an additional 3 weeks following treatment cessation. | [552764] | Drug Info | |
| The Effect of Target Knockout, Knockdown or Genetic Variations | The potential role of the bcl-2 relative bcl-w as a physiological regulator of apoptosis in intestinal epithelia has been investigated. Immunoblots for bcl-w with new monoclonalantibodies revealed that it was expressed in the small intestine and colon, among other murine tissues, as well as in six h uMan t uMour cell lines of epithelial origin, including two colon carcinomalines. To assess whether bcl-w regulates either spontaneous or damage-induced apoptosis in the small intestine or colon, apoptosis in intestinal crypts of bcl-w -/- and wild-type mice was quantified microscopically on a cell positional basis. Spontaneous apoptosis within crypt epithelia was not significantly increased by loss of bcl-w, in either the small intestine or midcolon. However, after treatment with the cytotoxic drug 5-fluorouracil or with gamma-radiation, the bcl-w-null animals exhibited substantially more apoptosis than their wild-type counterparts in both tissues. The greatest enhancement of apoptosis attributable to the absence of bcl-w (up to sixfold) occurred in the small intestine. Hence, bcl-w is an important determinant of damage-induced apoptosis in intestinal epithelia, and unlike bcl-2, which regulates only colonic apoptosis, plays a major role in small intestinal epitheli uM | [552892] | |||
| References | |||||
| Ref 552892 | BCL-2 family antagonists for cancer therapy. Nat Rev Drug Discov. 2008 Dec;7(12):989-1000. doi: 10.1038/nrd2658. | ||||
| Ref 552764 | Initial testing (stage 1) of the BH3 mimetic ABT-263 by the pediatric preclinical testing program. Pediatr Blood Cancer. 2008 Jun;50(6):1181-9. | ||||
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