Progress in the Development of Eukaryotic Elongation Factor 2 Kinase (eEF2K) Natural Product and Synthetic Small Molecule Inhibitors for Cancer Chemotherapy

Abstract

Eukaryotic elongation factor 2 kinase (eEF2K or Ca2+/calmodulin-dependent protein kinase, CAMKIII) is a new member of an atypical α-kinase family different from conventional protein kinases that is now considered as a potential target for the treatment of cancer. This protein regulates the phosphorylation of eukaryotic elongation factor 2 (eEF2) to restrain activity and inhibit the elongation stage of protein synthesis. Mounting evidence shows that eEF2K regulates the cell cycle, autophagy, apoptosis, angiogenesis, invasion, and metastasis in several types of cancers. The expression of eEF2K promotes survival of cancer cells, and the level of this protein is increased in many cancer cells to adapt them to the microenvironment conditions including hypoxia, nutrient depletion, and acidosis. The physiological function of eEF2K and its role in the development and progression of cancer are here reviewed in detail. In addition, a summary of progress for in vitro eEF2K inhibitors from anti-cancer drug discovery research in recent years, along with their structure-activity relationships (SARs) and synthetic routes or natural sources, is also described. Special attention is given to those inhibitors that have been already validated in vivo, with the overall aim to provide reference context for the further development of new first-in-class anti-cancer drugs that target eEF2K.

Keywords: cancer therapy; eEF2K; enzyme inhibitors; medicinal chemistry; natural products; protein kinase; small molecules.

Figure 1

The effects that some typical tumor microenvironmental conditions have on eEF2K.

Figure 2

Some pathway effects of eEF2K on apoptosis in tumor cells.

Figure 3

The regulatory effects of eEF2K on the cell cycle, especially prevalent in cancers.

Figure 4

The structures of eEF2K inhibitors 1 and 2.

Scheme 1

General synthesis of 2 and related analogues.

Scheme 2

General synthesis of pyrido[2,3-d]pyrimidine-2,4-dione analogues.

Figure 5

The structures of active pyrido[2,3-d]pyrimidine-2,4-diones 5, 10, and the related PROTAC lead, 11.

Scheme 3

General synthesis of 5,6-dihydro-4H-1,3-selenazine analogues (TS series).

Figure 6

Structures of the active and relatively stable 5,6-dihydro-4H-1,3-selenazines, 14 and 15.

Figure 7

The structures of thieno[2,3-b]pyridine analogues.

Scheme 4

General synthesis of thieno[2,3-b]pyridine analogues.

Figure 8

The structures of active β-phenylalanine derivatives and analogues, including 22 and 28.

Scheme 5

General synthesis of β-phenylalanine analogues.

Figure 9

The structure of fluoxetine, an approved SSRI drug later evaluated as an eEF2K inhibitor.

Figure 10

Structures of some natural products that are eEF2K inhibitors (30–35).

Figure 11

The structures of the PLK1/eEF2K dual-targeting inhibitor, 44.

Scheme 6

Synthesis route to 1-(4-(2-substituted-pyridin-4-yl)-3-substituted-phenyl)-3-phenylurea PLK1/eEF2K dual-targeting inhibitors.

Figure 12

Structures of two active eEF2K inhibiting sorbicillinoid natural products (45 and 46) from the sponge-derived fungus Penicillium chrysogenum.

Figure 13

The structures of geldanamycin (47) and a synthetic derivative, 17-AAG (48).

Figure 14

Structures of the eEF2K activators ritonavir, lopinavir, and resveratrol (49–51).