Organoboronic acids/esters as effective drug and prodrug candidates in cancer treatments: challenge and hope.

Boronic acids/esters have recently emerged in the field of medicinal and pharmaceutical research due to their exceptional oxophilicity, low toxicity, and unique structure. They are known as potent enzyme inhibitors, cancer therapy capture agents, and can mimic certain types of antibodies to fight infections. They have been designed and developed into drugs, and this approach has emerged in the last 20 years. Five boronic acid drugs have been approved by the FDA and Health Canada, two of which are used to treat cancer, specifically multiple myeloma. The purpose of this review is to investigate boronic acid/ester derivatives as potential pharmaceutical agents as well as the mechanism of action. It will concentrate on six types of cancer: multiple myeloma, prostate cancer, breast cancer, lung cancer, cervical cancer, and colon cancer. Some newly developed boron-containing compounds have already demonstrated highly promising activities, but further investigation is required before final conclusions can be drawn.

Pim kinase inhibitors in cancer: medicinal chemistry insights into their activity and selectivity.

The oncogenic Pim kinase proteins (Pim-1/2/3) regulate tumorigenesis through phosphorylating essential proteins that control cell cycle and proliferation. Pim kinase is a potential chemotherapeutic target in cancer and its inhibition is currently the focus of intensive drug design and development efforts. The distinctive presence of proline amino acids in the hinge region provides an opportunity to inhibit Pim kinase while conserving the physiological functions of other kinases and reducing the toxicity profiles of the inhibitors. Various Pim kinase inhibitors have been clinically evaluated for the treatment of hematological cancers, yet none has reached the clinic. In this review, we discuss the design and development of selective and potent Pim inhibitors with novel chemotypes focusing on structural features essential for high potency and selectivity.

Amino-carboxamide benzothiazoles as potential LSD1 hit inhibitors. Part I: Computational fragment-based drug design.

The lysine specific demethylase enzyme LSD1 regulates the function of histone proteins in cells through the demethylation of specific lysine amino acid residues. Being overexpressed in various cancers, LSD1 is considered as a validated target for cancer treatment. In this study, we describe the discovery of novel LSD1 inhibitors using computational fragment-based drug design approach. Structure-based screening of the Maybridge Ro3 2000 Diversity Fragment Library had identified two sets of fragments that bind to two different regions within the LSD1 active site. De Novo and Multiple Copy Simultaneous search (MCSS) docking, ligand efficiency (LE), and binding energy calculations (BE) had assisted the selection of the best scoring fragments that were grown to produce lead-like compounds. The final grown compounds were docked into the active site of the enzyme using flexible docking and their total binding energies were calculated in order to aid the selection of potential LSD1 inhibitors that will be synthesized and biologically evaluated. Six compounds were synthesized and biologically tested, of which two had showed a promising activity against LSD1. Compound 37, with an amino-carboxamide benzothiazole scaffold, showed the best inhibitory activity with an IC50 value of 18.4 µM. Compound 37 was chosen as an LSD1 hit inhibitor worthy of further optimization.