Drug discovery targeting p21-activated kinase 4 (PAK4): a patent review

ABSTRACT

Introduction: The Ser/Thr protein kinase PAK4 is a downstream regulator of Cdc42, mediating cytoskeleton remodeling, and cell motility, and inhibiting apoptosis and transcriptional regulation. Nowadays, efforts in PAK4 inhibitor development are focusing on improving inhibitory selectivity, cellular potency, and in vivo pharmacokinetic properties, and identifying the feasibility of immunotherapy combination in oncology therapy.

Areas covered: This review summarized the development of PAK4 inhibitors that reported on patents in the past two decades. According to their binding features, these inhibitors were classified into type I, type I 1/2, and PAMs. Their designing ideas and SAR were elucidated in this review. Moreover, synergistic therapy of PAK4 inhibitors with PD-1/PD-L1 or CAR-T were also summarized .

Expert opinion: In the past years, preclinical and clinical studies of PAK4 inhibitors ended in failure due to poor selectivity, cellular activity, or pharmacokinetic issues. There are researchers questioning the reliability of PAK4 as a drug target, particularly PAK4-related therapy is concerned with the distinguishment of the non-kinase functions and catalytic functions triggered by PAK4 phosphorylation. Meanwhile, synergistic effects of PAK4 inhibitors with PD-1/PD-L1 and CAR-T immunotherapy shed light for the development of PAK4 inhibitors.

KEYWORDS:

• P21-activated kinase 4
• kinase inhibitor
• patent
• solid tumor
• combination immunotherapy

Article highlights

• In this review, PAK4 inhibitors recorded in patents during the past 20 years were summarized for solid tumor and blood cancer treatments.

• Designing principles of PAK4 inhibitors were elucidated based on patents and related research articles.

• PAK4 non-kinase function was introduced and remarked, which is worthy to be considered for further pharmacological research.

• Possible side effects were also revealed by outlining different scaffolds of PAK4 inhibitors, which appeared to be a challenge for PAK4 inhibitor development.

Declaration of interest

M Cheng is the primary patent applicant of CN107652273, CN108239071 and CN111072640, which was cited in the manuscript. 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants, or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The work was financially supported by the National Natural Science Foundation of China (grant number 81872752 to M.C.; grant number 22077086 to J.W.), the Overseas Expertise Introduction Project for Discipline Innovation (grant number: D20029 to M.C.), the Program for Innovative Talents of Higher Education of Liaoning (grant number 2012520005 to J.W.), and Foundation from Education Department of Liaoning (grant number 2020LJC05 to J.W.).