Background: To circumvent Warburg effect, several clinical trials for different cancers are utilising a combinatorial approach using metabolic reprogramming and chemotherapeutic agents including metformin. The majority of these metabolic interventions work via indirectly activating AMP-activated protein kinase (AMPK) to alter cellular metabolism in favour of oxidative phosphorylation over aerobic glycolysis. The effect of these drugs is dependent on glycaemic and insulin conditions. Therefore, development of small molecules, which can activate AMPK, irrespective of the energy state, may be a better approach for triple-negative breast cancer (TNBC) treatment. Methods: Therapeutic effect of SU212 on TNBC cells was examined using in vitro and in vivo models. Results: We developed and characterised the efficacy of novel AMPK activator (SU212) that selectively induces oxidative phosphorylation and decreases glycolysis in TNBC cells, while not affecting these pathways in normal cells. SU212 accomplished this metabolic reprogramming by activating AMPK independent of energy stress and irrespective of the glycaemic/insulin state. This leads to mitotic phase arrest and apoptosis in TNBC cells. In vivo, SU212 inhibits tumour growth, cancer progression and metastasis. Conclusions: SU212 directly activates AMPK in TNBC cells, but does not hamper glucose metabolism in normal cells. Our study provides compelling preclinical data for further development of SU212 for the treatment of TNBC.

Small molecule tyrosine kinase inhibitors (TKI) have revolutionized cancer treatment and greatly improved patient survival. However, life-threatening cardiotoxicity of many TKIs has become a major concern. Ponatinib (ICLUSIG) was developed as an inhibitor of the BCR-ABL oncogene and is among the most cardiotoxic of TKIs. Consequently, use of ponatinib is restricted to the treatment of tumors carrying T315I-mutated BCR-ABL, which occurs in chronic myeloid leukemia (CML) and confers resistance to first- and second-generation inhibitors such as imatinib and nilotinib. Through parallel screening of cardiovascular toxicity and antitumor efficacy assays, we engineered safer analogs of ponatinib that retained potency against T315I BCR-ABL kinase activity and suppressed T315I mutant CML tumor growth. The new compounds were substantially less toxic in human cardiac vasculogenesis and cardiomyocyte contractility assays in vitro. The compounds showed a larger therapeutic window in vivo, leading to regression of human T315I mutant CML xenografts without cardiotoxicity. Comparison of the kinase inhibition profiles of ponatinib and the new compounds suggested that ponatinib cardiotoxicity is mediated by a few kinases, some of which were previously unassociated with cardiovascular disease. Overall, the study develops an approach using complex phenotypic assays to reduce the high risk of cardiovascular toxicity that is prevalent among small molecule oncology therapeutics. Significance: Newly developed ponatinib analogs retain antitumor efficacy but elicit significantly decreased cardiotoxicity, representing a therapeutic opportunity for safer CML treatment.

Heterocyclic compounds play a central role in drug development research and are contained in most pharmaceuticals on the market. Quinazoline and thiohydantoin are heterocycles and hold very prominent positions due to their diverse pharmacological profiles. While quinazolines fused with other heterocyclic units are already found in various clinically used pharmaceuticals, fused quinazoline-thiohydantoin frameworks have yet to be described since no synthetic approaches have been reported so far. Here, we present the development of a highly efficient, operationally simple, and fully metal-free three-step domino reaction towards fused heterocycles using readily available starting materials. Merging the novel three-step domino reaction and a dehydrogenation step in one pot leads to atom-economical, expeditious, and high-yielding (up to 92%) organic synthesis of unprecedented quinazoline-thiohydantoin fused frameworks. This new class of fused heterocycles features high in vitro activities and selectivities against multidrug-resistant P glycoprotein-overexpressing CEM/ADR5000 leukemia cells (IC50 down to 0.127 µM). It exceeds the potency of the clinical reference drug doxorubicin (IC50 23.27 µM). Furthermore, nuclear localization of Myocardin-related transcription factor A (MRTF-A, a.k.a. Megakaryoblastic Leukemia MKL1) as a tumor biomarker and driver of tumor resistance was decreased upon administration of quinazoline-thiohydantoin fused heterocycles. The developed straightforward synthetic approach enables the easy and direct formation of model drugs to overcome multidrug resistance in leukemia cells.

Osteosarcoma, the most common primary bone malignancy in adolescents and young adults, is still marked by poor long-term survival and high mortality. Although immune checkpoint blockade (ICB) has transformed treatment for several cancers, its benefit in osteosarcoma has been minimal, largely due to osteosarcoma’s “immune-cold” phenotype characterized by scarce tumor-infiltrating lymphocytes. Novel strategies are urgently needed to overcome this resistance. Y-box binding protein 1 (YB-1), a pro-oncogenic member of the cold-shock protein superfamily, represents a promising target to sensitize osteosarcoma to ICB. In this study, we evaluate SU056, a small-molecule YB-1 inhibitor, which both suppressed intrinsic osteosarcoma tumor growth and remodeled the tumor microenvironment. SU056 treatment markedly reduced immunosuppressive populations, including regulatory T cells and M2-polarized tumor-associated macrophages, while enhancing the infiltration of granzyme B-positive cytotoxic CD8+ T and NK cells. Combination therapy with SU056 and anti–PD-1 blockade produced superior tumor growth inhibition and significantly prolonged survival compared with either monotherapy. These findings highlight SU056 as a potent immunomodulatory agent and support its coadministration with ICB as a promising therapeutic approach for osteosarcoma.

Mycobacterium-w (Mw) was shown to boost adaptive natural killer (ANK) cells and protect against COVID-19 during the first wave of the pandemic. As a follow-up of the trial, 50 healthcare workers (HCW) who had received Mw in September 2020 and subsequently received at least one dose of ChAdOx1 nCoV-19 vaccine (Mw + ChAdOx1 group) were monitored for symptomatic COVID-19 during a major outbreak with the delta variant of SARS-CoV-2 (April–June 2021), along with 201 HCW receiving both doses of the vaccine without Mw (ChAdOx1 group). Despite 48% having received just a single dose of the vaccine in the Mw + ChAdOx1 group, only two had mild COVID-19, compared to 36 infections in the ChAdOx1 group (HR-0.46, p = 0.009). Transcriptomic studies revealed an enhanced adaptive NK cell-dependent ADCC in the Mw + ChAdOx1 group, along with downregulation of the TLR2-MYD88 pathway and concomitant attenuation of downstream inflammatory pathways. This might have resulted in robust protection during the pandemic with the delta variant.

PDF - 68K, Figure legend for Supplementary Figure 1.