Background: Cancer stem cells (CSCs) are highly tumorigenic, chemotherapy-resistant, tumor growth-sustaining, and are implicated in tumor recurrence. Previous studies have shown that lysine-specific histone demethylase 1A (KDM1A) is highly expressed in several human malignancies and CSCs. However, the role of KDM1A in CSCs and the therapeutic potential of KDM1A inhibitors for the treatment of the advanced thyroid cancer are poorly understood. Methods: Firstly, KDM1A was identified as an important epigenetic modifier that maintained the stemness of thyroid cancer through a mini histone methylation modifier screen and confirmed in thyroid cancer tissues and cell lines. RNA sequence was performed to discover the downstream genes of KDM1A. The underlying mechanisms were further investigated by ChIP, IP and dual luciferase reporter assays, gain and loss of function assays. Results: Here we report that KDM1A regulates the stemness of thyroid cancer and promotes thyroid cancer progression via the Wnt/β-catenin pathway. Mechanistically, KDM1A down-regulates two antagonists of the canonical Wnt pathway, APC2 and DKK1, by demethylating H3K4me1/2 of the APC2 promoter region and the nonhistone substrate HIF-1α, resulting in the inhibition of APC2 transcription and the activation of the HIF-1α/microRNA-146a/DKK1 axis. Importantly, we also demonstrate that GSK-LSD1, a highly selective inhibitor of KDM1A, significantly inhibits thyroid cancer progression and enhances the sensitivity of thyroid cancer to chemotherapy. Conclusions: KDM1A plays an important role in thyroid cancer progression and maintains stemness, our study provides a new strategy for the therapy of advanced thyroid cancer.

Janus kinase 1 (JAK1) is a potential target for the treatment of rheumatoid arthritis (RA). In this study, the introduction of a spiro ring with a difluoro-substituted cyclopropionamide resulted in the identification of TUL01101 (compound 36) based on a triazolo[1,5-a]pyridine core of filgotinib. It showed excellent potency on JAK1 with an IC50 value of 3 nM and exhibited more than 12-fold selectivity for JAK2 and TYK2. Whole blood assay also demonstrated the high activity and selectivity (37-fold for JAK2). At the same time, TUL01101 also demonstrated excellent metabolic stability and pharmacokinetics (PK) profiles were assayed in three species (mouse, rat, and dog). Moreover, it has been validated for effective activity in the treatment of RA both in collagen-induced arthritis (CIA) and adjuvant-induced arthritis (AIA) models, with low dose and low toxicity. Now, TUL01101 has progressed into phase I clinical trials.

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