Betty Lam

POLO-LIKE KINASE INHIBITORS

Polo-like kinases (PLKs) are a family of serine/threonine kinases that play crucial roles in multiple stages of mitosis. PLK1 is the most studied member of the family. It is overexpressed in a wide spectrum of cancer types and is a promising target in oncology. Most of PLK1 inhibitors are ATP-competitive. Despite the structural similarities among various kinases, several inhibitors are selective. Some areas of the PLK1 active site are important for selectivity against other kinases. These include a small pocket formed by Leu 132 in the hinge region, a bulky phenylalanine and a small cysteine at the bottom and in the roof of the ATP pocket, respectively, and an unusual concentration of positively charged residues in the solvent-exposed region. Many ATP-competitive inhibitors are heterocyclic systems able to interact with the unique features of the PLK1 binding site. Other inhibitors target regions outside the ATP pocket, such as the substrate binding domain or a hydrophobic pocket, formed when the kinase is in the inactive conformation. An alternative approach to obtain specificity and to overcome drug resistance often associated with kinase inhibitors is the inhibition of the polo-box domain (PBD) of PLK1. The PBD is unique for the family of PLKs and is essential for PLK functions; so it is a useful target for the development of selective and potent inhibitors for clinical uses. In this review some PLK inhibitors are reported, focusing on chemical structures, structure-activity-relationships (SAR) and biological activities. The great potential of these compounds could open promising perspectives. Moreover, a combination of polo-like kinases inhibitors with other anticancer drugs might offer new opportunities for cancer therapy.

Discovery of TAK-960: An orally available small molecule inhibitor of polo-like kinase 1 (PLK1).

Using structure-based drug design, we identified and optimized a novel series of pyrimidodiazepinone PLK1 inhibitors resulting in the selection of the development candidate TAK-960. TAK-960 is currently undergoing Phase I evaluation in adult patients with advanced solid malignancies.

Structure-based design of pyridopyrimidinediones as dipeptidyl peptidase IV inhibitors

Dipeptidyl peptidase IV (DPP-4) inhibitors have been shown to enhance GLP-1 levels and thereby improve hyperglycemia in type II diabetes. From a small fragment hit, using structure-based design, we have discovered a new class of non-covalent, potent and selective DPP-4 inhibitors.

Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).

Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.

Structure-based design and SAR development of 5,6-dihydroimidazolo[1,5-f]pteridine derivatives as novel Polo-like kinase-1 inhibitors.

Using structure-based drug design, we identified a novel series of 5,6-dihydroimidazolo[1,5-f]pteridine PLK1 inhibitors. Rational improvements to compounds of this class resulted in single-digit nanomolar enzyme and cellular activity against PLK1, and oral bioavailability. Compound 1 exhibits >7 fold induction of phosphorylated Histone H3 and is efficacious in an in vivo HT-29 tumor xenograft model.