A Bcl-xL inhibitor
Ki: 6 nM for BCL-2 TR-FRET
A-1331852 is a potent and selective inhibitor of BCL-XL.
Apoptosis is reported to be regulated by a family of closely related proteins exemplified by B cell lymphoma protein 2 (BCL-2), which is the first discovered family member. BCL-2 family proteins are divided by one to four BCL-2 homology motifs and can be further subdivided into pro- and antiapoptotic subsets.
In vitro: A-1331852 was identified as a potent BCL-XL inhibitor demonstrating cellular activity 10- to 50-fold more potent than its analog A-1155463 and the previouly reported BCL-XL inhibitor, navitoclax, respectively. Moreover, A-1331852 could selectively disrupt BCL-XL–BIM complexes and induce the apoptosis hallmarks in BCL-XL–dependent Molt-4 cells with median IC50 values in the low nanomolar range but did not affect MEF cells without BAK or BAX [1].
In vivo: Previous animal study found that A-1331852 could demonstrate antitumor efficacy in the Molt-4 xenograft model, such as tumor regressions as a single agent. In addition, in the NCI-H1963.FP5 xenograft model of SCLC, it was found that A-1331852 combined with venetoclax was able to recapitulate the efficacy of navitoclax [1].
Clinical trial: Up to now, A-1331852 is still in the preclinical development stage.
Reference:
[1] Leverson JD et al.? Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy. Sci Transl Med. 2015 Mar 18;7(279):279ra40. doi: 10.1126/scitranslmed.aaa4642.
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Cell experiment: |
SCLC and AML cell lines are incubated with increasing concentrations of navitoclax, venetoclax, or A-1155463 for 48 hours before assessing cell viability. Cell killing EC50 values are calculated[1]. |
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Animal experiment: |
Mice: The growth inhibition of established tumors in SCID-bg mice is studied. A-1331852 is administered orally daily for 14 days at 25 mg/kg and RP-56976 is administered intravenously at 7.5 mg/kg. The change of tumor volume is monitored daily[1]. |
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参考文献: [1]. Leverson JD, et al. Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy. Sci Transl Med. 2015 Mar 18;7(279):279ra40. |
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