Structure-guided design of Structure-guided design of a selective BCL-Xa selective BCL-XLL

inhibitor inhibitor

Tianlei Sun2013/11/26

Why search for inhibitors of BCL-XLWhy search for inhibitors of BCL-XL

BCL-XL is anti-apoptotic protein.

Enhancing apoptotic responses of cancer cells by inhibiting BCL-XL.

Instead of inhibiting multiple anti-apoptotic BCL-2 family members, a BCL-XL–selective inhibitor would be expected to minimize the toxicity to normal tissues.

How they didHow they didHigh-throughput screen

Fig.1 Compound 1a identified from the screen and close analog 1b

Fig.2 Two potential binding modes for 1b in the hydrophobic groove of BCL-XL.

Fig.3 Structure of compound2. Fig.4 binding mode of 2 in the BCL-XL hydrophobic groove

Fig.5 interaction network between the benzothiazole moiety of 2 and Ser106, Asp107 and Leu108 in the P2 pocket.

Fig.6 Position of Phe105 in relation to the furan moiety of 2 and the electrostatic interaction between Arg139 and the acylsulfonamide group of 2.

PymolPymol 演示演示