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Targeting sphingosine kinase 1 (SphK1) has become a novel strategy for the treatment of inflammatory bowel disease and cancer

Activation of the stimulator of interferon gene (STING) has emerged as an exciting immuno-oncology therapeutic strategy; however, the first-generation STING agonists, cyclic dinucleotide (CDN) analogues, have suffered from many disadvantages and failed in clinical trials. Therefore, non-CDN small-molecule STING agonists are urgently needed. In view of the unique structure of the high potency of dimeric amidobenzimidazole STING agonist 5, a structural elaboration was conducted by modifying several structural hotspots of this scaffold. Triazole 40 was identified as a new potent STING activator, possessing EC50 values of 0.24 and 39.51 μM for h- and m-STING, respectively. This compound has a slightly better pharmacokinetic profile and is >20-fold more aqueously soluble than 5. It activated the STING signaling dramatically by directly binding and stabilizing all h-STING isoforms and m-STING. In vivo, intermittent administration of 40 was found to have significant antitumor efficacy with good tolerance in two mouse tumor models.

Pyruvate dehydrogenase kinases (PDKs) are overexpressed in most cancer cells and are responsible for aberrant glucose metabolism. We previously described bis(4-morpholinyl thiocarbonyl)-disulfide (JX06, 16) as the first covalent inhibitor of PDK1. Here, on the basis of the scaffold of 16, we identify two novel types of disulfide-based PDK1 inhibitors. The most potent analogue, 3a, effectively inhibits PDK1 both at the molecular (kinact/Ki = 4.17 × 103 M–1 s–1) and the cellular level (down to 0.1 μM). In contrast to 16, 3a is a potent and subtype-selective inhibitor of PDK1 with >40-fold selectivity for PDK2–4. 3a also significantly alters glucose metabolic pathways in A549 cells by decreasing ECAR and increasing ROS. Moreover, in the xenograft models, 3a shows significant antitumor activity with no negative effect to the mice weight. Collectively, these data demonstrate that 3a may be an excellent lead compound for the treatment of cancer as a first-generation subtype-selective and covalent PDK1 inhibitor.

Upregulation of pyruvate dehydrogenase kinase (PDHK) has been observed in a variety of cancers. Inhibition of PDHK offers an attractive opportunity for the development of novel cancer therapies. To obtain novel PDHK inhibitors, we took advantage of the homology of the ATP-binding pocket between Heat Shock Protein 90 (HSP90) and PDHK, and utilized 4,5-diarylisoxazole based HSP90 inhibitor for structural design. Our efforts led to the identification of 5k that inhibited PDHK1 with an IC50 value of 17 nM, which, however, showed marginal cellular activity. Further structural optimization resulted in compound 11a with improved cellular activity which could effectively modulate the metabolic profile of cancer cells and lead to the inhibition of cancer cell proliferation, evidenced by the increased oxidative phosphorylation and decreased glycolysis and associated oxidative stress. Our results suggested 11a as an excellent lead compound and a favorable biological tool to further evaluate the therapeutic potential of PDHK and HSP90 dual inhibitors in the treatment of cancer.