HOT TOPICS IN PHARMACOGNOSY: So What About the Other Half of Kinase Inhibitor Activities?

By David J. Newman, DPhil

INTRODUCTION

Although we have been inundated over the years with stories of the successes with inhibiting protein tyrosine kinases (aka PTKs) and their chemical cousins, based on other amino acids such as serine or threonine as the basis of drugs against a variety of diseases predominately in cancer, little has been “seen of their other partner in crime,” the protein tyrosine phosphatase whose job is to regenerate the kinase in due course. Do they have potential as targets in their own right where the ability to inhibit specific phosphatase(s) may well lead to a drug candidate?

DISCUSSION

As a result of a very interesting recent paper in the Journal of Medicinal Chemistry by Hu et al.¹ the potential of inhibitors of this enzyme as a potential cancer treatment against triple-negative breast cancer (TNBC) was demonstrated. What was fascinating about this particular study was that the agent(s) initially identified were from a series of naturally occurring jamunones. Specifically, the chromanone Jamunone M (1) was reported by the same Chinese investigators following isolation from Eugenia jambolana seeds, and who had reported their inhibitory activity against PTP1B four years ago as basically a phytochemical exercise with one target enzyme PTP1B.² At that time the reports covered the isolation, identification of knowns and structural determinations of other isolated compounds. Some of those compounds exhibited quite reasonable potencies (IC₅₀) in the 0.42 to 3.2 µM range, comparable to ursolic acid, a well-known triterpenoid with multiple pharmacological activities.³

In the recent 2021 paper, Hu et al. demonstrated that compound 1 demonstrated selectivity against breast cancer cells versus other cancer cell lines and also normal cells, with better activity against TNBC cells than the “regular” breast cancer cell line MCF7. Further investigations demonstrated that JM (1) specifically inhibited the enzymatic activity and also the protein expression of PTP1B, with subsequent deactivation of the PI3K/Akt pathways. Then to add to their “case,” an in vivo assay against the TNBC cell line MDA-MB-231 demonstrated significant inhibition of tumor volume/weights at 30 mg/kg over 20 days with no significant weight loss. Since scalable synthetic schemes were part of this paper, the potential for further studies is high.

If one now moves away from cancer studies and looks at the disease states where PTP1B inhibition is a “useful” process, then inhibitors of this enzyme appear as drug candidates and actual approved drugs in diseases not “formally” related to cancer. One such major area is in the treatment of diabetes II, and it would appear that although inhibition of this phosphatase is a factor in a number of experimental and approved drug candidates, there appears to be a lack of testing of some of these antidiabetic II agents in cancer studies.

 

The very interesting aspect of aplidine is that PharmaMar commenced clinical trials looking at toxicity with the aim of perhaps leading to another (repurposed!) use for this compound which has only been approved for multiple myeloma in Australia (late 2018).

 

A recent study of natural PTP1B inhibitors by the Le group from Vietnam⁴ studying isolated compounds from Polygonum cuspidatum led to the identification of 10 active principles. Of these 10, compound 2 (identified as tri-cuspidatin B) had an IC₅₀ value of 6.3 µM, a K_i value of 51.4 µM and demonstrated mixed-competitive kinetics when tested against PTP1B but demonstrated increased uptake of glucose in adipocytes at 5 and 10 µM levels, possibly due to inhibition of PTP1B enzymes.

Following on from the impact on glucose metabolism above, the 2020 paper by Rocha et al.⁵ discussed the PTP1B inhibition potential of the drug lobeglitazone (3) which was approved in Korea in 2013 as an antihyperglycemic agent via PPAR-γ agonism. This is a very interesting paper as it discusses a fair number of related agents that are useful leads to antidiabetic structures but also points out that these agents appear to be non-competitive inhibitors of PTP1B and have indications that they may bind at an allosteric site in this phosphatase.

Structures

 

THOUGHT-PROVOKING QUESTIONS

Just to (perhaps) throw what in the UK is known as “a spanner in the works,” meaning identifying a potential problem with published data, a paper in 2020 by Rivera-Chavez et al.⁶ pointed out that most of the published work on PTP1B inhibitors used a truncated form of the human enzyme (PTP1B_1-300) rather than the full-length enzyme with 400 residues.

In their studies, they found interesting inhibitory compounds from an extract of the fungus Aspergillus terreus (IQ-046), most of which were known natural products, including butyrolactone I and IV and, interestingly, lovastatin (aka mevinolin) and chrysamide B (structures not shown). From details given in the paper, it is noted that currently only five other natural products have been shown to be inhibitors of the full-length enzyme, which brings up the “spanner in the works!” viz: questions about the comparison of relationships established using the “normal” truncated enzyme.

The data in the first paper above with TNBCs is “selfcontained” but further studies need to take into account the probable presence of other important binding sites on what was thought to be a “common target.”

Thus, the “take home lesson is”: any natural products chemist wishing to study the effects of their compound(s) by using a biological assay with an isolated enzyme, needs to consider what is known biochemically and physiologically about the enzyme they are using and ask the relevant questions of any biologist with whom they are collaborating.

 

Thus, the “take home lesson is”: any natural products chemist wishing to study the effects of their compound(s) by using a biological assay with an isolated enzyme, needs to consider what is known biochemically and physiologically about the enzyme they are using and ask the relevant questions of any biologist with whom they are collaborating.

 

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