Tasquinimod

The alarmins, S100A8 (A8) and S100A9 (A9), are low molecular weight proteins belonging to the S100 protein family. A8 and A9 are secreted into the extracellular space and plasma, in which they interact with Toll-like receptor 4, receptor for advanced glycation end products, and CD33. In these studies, we determined the preclinical efficacy of tasquinimod (TQ) against advanced myeloproliferative neoplasm (MPN) cell lines and patient-derived (PD) CD34+ blastic phase (BP; >5% blasts in the peripheral blood) MPN cells. TQ induced loss of viability in cell lines and PD MPN-BP cells, but not in normal CD34+ progenitor cells. In TQ-treated PD MPN–acute myeloid leukemia (AML) cells, RNA-sequencing analysis showed negative enrichment of the gene sets of MYC and E2F targets, interleukin-6–JAK-STAT3 signaling, and of inflammatory response. In phenotypically defined, PD CD34+ MPN-BP stem progenitor cells, cytometry by time-of-flight analysis showed that TQ reduced expression of proteins including A8, A9, and myeloperoxidase, while increasing expression of Growth Factor Independence 1 (GFI1), p21, and cleaved Poly(ADP-ribose) polymerase (PARP). Cotreatment with TQ and ruxolitinib or Bromodomain and extraterminal domain (BET) inhibitor induced synergistic lethality in advanced MPN-BP cells. Monotherapy with TQ significantly improved survival of immune-depleted NOD scid gamma (NSG) mice engrafted with PD xenograft (PDX) cells of MPN-AML. Notably, cotreatment with TQ and ruxolitinib or OTX015 induced significantly greater survival than treatment with single agents in the NSG mice engrafted with the PDX cells. These findings clearly demonstrate the preclinical efficacy of TQ in advanced MPN-BP cells and create the rationale to further interrogate the efficacy of TQ-based combinations with the current, frontline therapies or novel agents in advanced MPNs with excess blasts.

Ataxia-telangiectasia is a neurodegenerative disorder characterised by ATM deficiency and aberrant nuclear accumulation of Histone deacetylase 4 (HDAC4) in Purkinje neurons. Targeting HDAC4 has thus emerged as a promising therapeutic strategy. Here, we employed a drug-repositioning approach to identify new HDAC4 modulators from an EMA-approved compound library. In silico screening selected asenapine, a second-generation antipsychotic, through consensus scoring across four independent docking functions and low predicted binding free energy (ΔG), positioning it among the most thermodynamically stable candidates. Surface plasmon resonance analysis confirmed high-affinity binding to immobilised HDAC4, enabling extraction of kinetic and thermodynamic parameters that characterise the allosteric mechanism underlying HDAC4-asenapine complex formation. Competitive assay with tasquinimod, a known HDAC4 modulator, revealed that asenapine exhibits higher affinity supporting its candidacy for further pharmacological development. These findings underscore the utility of combining repositioning pipelines with real-time affinity quantification to accelerate the discovery of selective HDAC4-targeted therapeutics for Ataxia-Telangiectasia.