apogossypolone and Neoplasms

The myeloid leukemia cell differentiation protein (Mcl-1) is an anti-apoptotic protein of the B-cell lymphoma 2 (Bcl-2) family, which regulates cellular apoptosis. Mcl-1 expression plays a key role in survival of cancer cells and therefore serves as a promising target in cancer therapy. Besides, its importance as a cancer target, various peptides and small-molecule inhibitors have been successfully designed and synthesized, yet no Mcl-1 inhibitor is approved for clinical use. However, recent development on the understanding of Mcl-1's role in key cellular processes in cancer and an upsurge of reports highlighting its association in various anticancer drug resistance supports the view that Mcl-1 is a key target in various cancers, especially hematological cancers. This review compiles structures of a variety of inhibitors of Mcl-1 reported to date. These include inhibitors based on a diverse range of heterocycles (e.g. indole, imidazole, thiophene, nicotinic acid, piperazine, triazine, thiazole, isoindoline), oligomers (terphenyl, quaterpyridine), polyphenol, phenalene, anthranilic acid, anthraquinone, macrocycles, natural products, and metal-based complexes. In addition, an effort has been made to summarize the structure activity relationships, based on a variety of assays, of some important classes of Mcl-1 inhibitors, giving affinities and selectivities for Mcl-1 compared to other Bcl-2 family members. A focus has been placed on categorizing the inhibitors based on their core frameworks (scaffolds) to appeal to the chemical biologist or medicinal chemist.

Topics: Antineoplastic Agents; Cell Proliferation; Drug Development; Heterocyclic Compounds; Humans; Molecular Structure; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasms

A balance of Bcl-2 family proteins dictates cell survival or death, as the interactions between these proteins regulate mitochondrial apoptotic signaling pathways. However, cancer cells frequently show upregulation of pro-survival Bcl-2 proteins and sequester activated pro-apoptotic BH3-only proteins driven by diverse cytotoxic stresses, resulting in tumor progression and chemoresistance. Synthetic molecules from either structure-based design or screening procedures to engage and inactivate pro-survival Bcl-2 proteins and restore apoptotic process represent a chemical biological means of selectively killing malignant cells. 17 years ago, one of us reviewed on the discovery of novel Bcl-2 targeted agents [1]. Here we revisit this area and examine the progress and current status of small molecule Bcl-2 inhibitor development, demonstrating the Bcl-2 family as a valid target for cancer therapy and providing successful examples for the discovery of inhibitors that target protein-protein interactions.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Drug Design; Humans; Neoplasms; Proto-Oncogene Proteins c-bcl-2

Targeting apoptosis is an attractive approach in cancer therapy. The BH3-only proteins of the BCL-2 family (having only the BCL-2 homology domain BH3) can trigger apoptosis by binding to the prosurvival members of this family and neutralizing their functional activity (sequestration of the proapoptotic Bcl-2 family members). The "BH3 mimetic" concept has prompted the development of small molecules capable of mimicking BH3-only proteins and thus inducing apoptosis. The prototype BH3 mimetic ABT-737 selectively targets the three prosurvival proteins BCL-XL, BCL-2, and BCL-W (but not MCL-1 or A1) and its oral derivative ABT-263 has proved promising in clinical trials. Some putative BH3 mimetics are also tested clinically while others are still being characterized. This article recapitulates the various known BH3 mimetics and presents the recent developments in the field. The latter include (i) the identification of molecular determinants responsible for the specific interactions between BH3 motifs and the binding grooves of prosurvival proteins and (ii) the characterization of new compounds and particularly BH3 mimetics that antagonize either selectively MCL-1 or BCL-2 or a broad range of prosurvival proteins. These data are critical advances toward the discovery of novel anticancer agents.

Topics: Amino Acid Motifs; Aniline Compounds; Antineoplastic Agents; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials as Topic; Drug Design; Drug Screening Assays, Antitumor; Gossypol; Humans; Indoles; Molecular Mimicry; Neoplasms; Peptide Fragments; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Pyrroles; Sulfonamides