A patent update on PDK1 inhibitors (2015-present)

ABSTRACT

Introduction: 3-Phosphoinositide-dependent kinase 1 (PDK1), the ‘master kinase of the AGC protein kinase family’, plays a key role in cancer development and progression. Although it has been rather overlooked, in the last decades a growing number of molecules have been developed to effectively modulate the PDK1 enzyme.

Areas covered: This review collects different PDK1 inhibitors patented from October 2014 to December 2018. The molecules have been classified on the basis of the chemical structure/type of inhibition, and for each general structure, examples have been discussed in extenso.

Expert opinion: The role of PDK1 in cancer development and progression as well as in metastasis formation and in chemoresistance has been confirmed by many studies. Therefore, the pharmaceutical discovery in both public and private institutions is still ongoing despite the plentiful molecules already published. The majority of the new molecules synthetized interact with binding sites different from the ATP binding site (i.e. PIF pocket or DFG-out conformation). However, many researchers are still looking for innovative PDK1 modulation strategy such as combination of well-known inhibitory agents or multitarget ligands, aiming to block, together with PDK1, other different critical players in the wide panorama of proteins involved in tumor pathways.

KEYWORDS:

• Allosteric inhibitors
• chemoresistance
• DFG-out inhibitor
• drug discovery
• metastasis
• 3-phosphoinositide-dependent kinase 1
• PDK1 inhibitor
• PIF-pocket inhibitor
• PH-domain inhibitor
• PI3K/PDK1/Akt pathway

Article highlights

• PDK1, generally referred to as the master kinase of the AGC family, is considered a compelling target in oncology; nevertheless, nowadays no selective PDK1 inhibitor is available for cancer therapy;

• PDK1 inhibitors patented from October 2014 to December 2018 are collected and classified according to the chemical structure/type of inhibition;

• Although the majority of patents concern newly synthesized chemical molecules for cancer therapy, innovative strategies of PDK1 inhibition are mentioned;

• The combined and simultaneous inhibition of other targets could represent the future strategy to better exploit the potential of PDK1 inhibition in anticancer therapy.

This box summarizes the key points contained in the article.

Declaration of interest

S. Sestito is part of a post-doc fellowship co-funded by the International Society of Drug Development, Srl (Milan, Italy) and POR FSE 2014-2020 Regione Toscana. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded.