Small-Molecule Inhibitors of the Mcl-1 Oncoprotein

Review Article

Austin J Anal Pharm Chem. 2014;1(3): 1015.

Small-Molecule Inhibitors of the Mcl-1 Oncoprotein

Lijia Chen1, Maryanna E. Lanning1 and Steven Fletcher1,2*

1Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, USA

2University of Maryland Greenebaum Cancer Center, Baltimore, MD, USA

*Corresponding author: :Steven Fletcher, Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, University of Maryland Greenebaum Cancer Center, USA

Received: September 18, 2014; Accepted: October 05, 2014; Published: October 10, 2014


Mcl-1, an anti-apoptotic member of the Bcl-2 protein family, has emerged as an especially attractive target for the development of next generation antineoplastics owing to its direct involvement in tumor genesis as well as its role in the resistance of many cancers to current anti-cancer therapies. The efficacy of Navitoclax against a range of different cancer models that are dependent on Bcl-xL and Bcl-2, two relatives of Mcl-1, indicates that the inhibition of Mcl-1 with small-molecules might also be a viable strategy to kill cancer cells by inducing apoptosis. Herein, we provide a comprehensive review of the most potent, Mcl-1 selective small-molecule inhibitors reported in the literature to date.


The Bcl-2 (B cell lymphoma 2) family of proteins, whose anti-apoptotic members include Bcl-2, Bcl-xL, Bcl-w, A1 and Mcl-1 (myeloid cell leukemia 1), are critical regulators of apoptosis, or programmed cell death [1]. A hallmark of cancer is the evasion of apoptosis, and many cancers are resistant to apoptosis due to overexpression of one or more of the Bcl-2 family members [2-4]. ABT-263 (Navitoclax), the clinical analogue of ABT-737, is a potent, dual inhibitor of Bcl-xL and Bcl-2, and is an effective killer of cancer cells over expressing these proteins [5]. However, Navitoclax exhibits limited activity against Mcl-1, such that cancer cells overexpressing Mcl-1 or both Bcl-xL and Mcl-1 are resistant to the drug [6]. Over expression of the Mcl-1 protein and/or amplification of the Mcl-1 gene have been linked to a variety of human cancers, including lung, breast, pancreatic, cervical and ovarian cancers, as well as leukemia and lymphoma [7-15]. Mcl-1 overexpression is directly responsible for the emerging resistance of various FDA-approved anti-cancer therapies, including vincristine [16], Taxol [16], gemcitabine [17] and cisplatin [18]. Importantly, down regulation of Mcl-1 by RNAi decreases tumor-igenicity in mouse xenograft models [17]. Taken together, these observations suggest that the inhibition of Mcl-1 by small-molecules might provide an alternative strategy to kill cancer cells by inducing apoptosis. With this in mind, the focus of this mini-review is on selective small-molecule inhibitors of the Mcl-1 protein; small-molecule inhibitors of Bcl-2, Bcl-xL and dual Bcl-xL/Mcl-1 inhibitors are reviewed elsewhere [19].

Like the other anti-apoptotic Bcl-2 proteins, there is a hydrophobic grove on the surface of Mcl-1 that engages the BH3 “death” domains of the pro-apoptotic Bcl-2 proteins, such as Bim, Bak and Bad. The BH3 domain is an amphipathic α-helix whose hydrophobic face recognizes four hydrophobic sub-pockets, p1, p2, p3 and p4, in the BH3-binding groove on Mcl-1, while a critical Asp on the polar face of the BH3 helix binds Arg263 of Mcl-1[1,20]. Figure 1A shows the crystal structure of the Bim-BH3–Mcl-1 complex, and Figure 1B is the BH3-binding groove on the surface of Mcl-1 with key binding regions and residues highlighted. Through this protein–protein interaction (PPI), Mcl-1 (and the other anti-apoptotic Bcl-2 proteins) “neutralizes” the cell-killing function of the pro-apoptotic Bcl-2 proteins. In this way, overexpression of Mcl-1 leads to the evasion of apoptosis and, hence, cancer. Small-molecules that can block this PPI through binding the hydrophobic groove on Mcl-1 are expected to counter this neutralization and allow the pro-apoptotic proteins to kill the cancer cell through restoring apoptosis. Dual Bcl-xL/ Mcl-1 inhibitors have been reported for about ten years, and these compounds are predicted and/or known to bind in some or all of these sub-pockets [19]. Although Bcl-xL-selective inhibitors, such as ABT- 737, have been identified, there have been limited advances towards the development of Mcl-1-selective inhibitors. In the last 18 months, however, some exciting advances have been made. This mini-review reports the recent progress in the discovery of small-molecules that selectively inhibit the Mcl-1 oncoprotein.