Inhibitors of the anti-apoptotic Bcl-2 proteins: a patent review

Abstract

Introduction: The B-cell lymphoma-2 (Bcl-2) family of proteins is central to the regulation of apoptosis, which is vital for proper tissue development and cellular homeostasis. Anti-apoptotic proteins, members of the Bcl-2 family, are an important survival factor for many cancers and their overexpression has been associated with tumor initiation, progression, and resistance to current anticancer therapies. Therefore, strategies seeking to antagonize the function of Bcl-2 anti-apoptotic proteins have been extensively studied for developing a novel cancer therapy.

Areas covered: This review covers research and patent literature of the last 15 years dealing with the discovery and development of inhibitors of the Bcl-2 protein family.

Expert opinion: The feasibility of disrupting protein-protein interactions between anti-apoptotic and pro-apoptotic proteins, members of the Bcl-2 family, using peptidomimetics and small-molecule inhibitors has been successfully established. Three small-molecule inhibitors have entered human clinical trials, which will allow the evaluation of this potential therapeutic approach in cancer patients. It will be important to gain a better understanding of pan and selective Bcl-2 inhibitors in order to facilitate future drug design efforts.

Figure 1

Extrinsic and intrinsic pathways of apoptosis. The onset of apoptosis is controlled by numerous interrelating processes. The extrinsic pathway is activated by external signals such as Fas ligand (FasL) or TRAIL, which act through death receptors. Subsequently Caspase-8 is activated through Fas-associated death domain (FADD). The intrinsic pathway is initiated by different signals, primarily extracellular stimuli. Mitochondria are an essential component of the intrinsic pathway and harbor an array of apoptotic factors. The Bcl-2 family is a primary regulator of the intrinsic pathway.

Figure 2

Members of the Bcl-2 family proteins; anti-apoptotic and pro-apoptotic. Conserved Bcl-2 homology domains (BH1-4) are denoted as is the carboxy-terminal hydrophobic (TM) domain.

Figure 3

(A) An eight-helix bundle creates a hydrophobic groove into which a BH3 peptide binds. The binding groove is formed largely by the helices α3 – 5. The example shown here is Bcl-x_L bound to Bim (PDB code: 3FDL). (B) The alignment of several BH3-only proteins. The conserved four hydrophobic residues and the Asp residue are highlighted by pink and light green respectively. (C) Structure of Mcl-1 (surface representation) bound to Bim (purple helix), which binds in a long, hydrophobic groove that has four non-contiguous hydrophobic pockets labeled h1 – h4 in the surface of Mcl-1 (PDB code: 2PQK). The five conserved residues are shown.

Figure 4

Peptidomimetics and small-molecule inhibitors (SMIs) targeting the canonical BH3-binding groove of anti-apoptotic proteins and antagonizing their function. (A) Crystal structure of the stapled peptide SAHB_D–in complex with Mcl-1 protein (PDB code: 3MK8). (B) Terphenyl-based Bak BH3 α-helical peptidomimetic as antagonist of Bcl-x_L (C) Superimposition of the x-ray structures of SMI ABT-737 (green, PDB code: 2YXJ) and Bim BH3 peptide (magenta, PDB code: 1PQ1) with Bcl-x_L protein.