The downregulation of Bcl xL has selleck Olaparib been shown to induce apoptosis and increase chemo sensitivity. ABT 737, the most well known member of a class of Bcl 2 family targeting compounds, and its orally active analog ABT 263, have activity as single agents in a subset of cancers that rely on Bcl 2/Bcl xL, but not Mcl 1, for survival. Because of the overexpression and overlapping functions Inhibitors,Modulators,Libraries of the Bcl 2 family proteins, Mcl 1 can compensate for the loss of the anti apoptotic function of Bcl 2/xL. Recent studies demonstrated that cancer cells rapidly develop resistance to ABT 737 through the up regulation of Mcl 1 and that the down regulation of Mcl 1 restores the sensi tivity to ABT 737. Mcl 1 reduction significantly enhances the sensitivity of cancer cells to ABT 737 and other chemotherapeutics.

Hence, these findings suggest that Mcl 1 overexpression may function as an additional survival mechanism to protect cancer cells against conventional therapies. Although the basic topology of BH3 domain hydro phobic binding groove is highly conserved among the prosurvival Bcl 2 family members such as Bcl 2, Bcl xL and Mcl 1, there is a selectivity in binding Inhibitors,Modulators,Libraries defined by the specific pattern of amino acid side chains located on the 2, 4, and 5 helices. This may explain why ABT 737 does not exhibit potency against Mcl 1. Be cause this hydrophobic groove normally accommodates the BH3 domain of pro apoptotic Bcl 2 proteins, it has been hypothesized that small molecules that bind to this BH3 binding groove in Bcl 2, Bcl xL, or Mcl 1 may be capable of blocking their heterodimerization with a subset of pro apoptotic members in the Bcl 2 protein family, such as Bax, Bid, and Bak.

This would expand the pool of free pro apoptotic effectors and, thus, induce apoptosis in cancer cells Inhibitors,Modulators,Libraries in which overexpressed Bcl 2, Bcl xL, or Mcl 1 provide survival cues. Hence, the development of BH3 mimetics could Inhibitors,Modulators,Libraries be a feasible and clinically effective approach to simultaneously inhibiting Bcl 2/xL and Mcl 1 functions. Indeed, several Inhibitors,Modulators,Libraries non peptidic small molecule BH3 mi metics designed to bind key domains in the hydrophobic BH3 binding groove have already been identified, the most extensively studied of which is the previously Ruxolitinib Sigma mentioned compound ABT 737. An alternative strategy to the disruption of this protein protein interaction centers on the observation that the BH3 domains of the pro apoptotic proteins become helical upon binding their anti apoptotic partners. Accordingly, small molecules have been designed to reproduce the relative projections of key hydrophobic side chains found on one face of the BH3 helix. For example, mimicry of Val74, Leu78, Ile81 on one face of the Bak BH3 helix has afforded potent Bcl xL inhibitors.