We have identified Tousled-like kinases (TLKs) as factors essential for chromatin assembly of newly synthesized DNA and preservation of genome integrity during chromatin replication. We further demonstrated a synergistic lethal relationship between de novo nucleosome assembly and checkpoint signaling, opening a new avenue for cancer therapy (Lee et al., Sci Adv 2018). We also extensively unearth compounds capable of triggering replication stress. We envision that the investigations will allow us to discover agents with low toxicity when treated alone, but synergistically toxic to cancer cells when combined with the chemotherapeutics agents or checkpoint inhibitors. The results will thus introduce innovative approaches to increase the anticancer therapy efficacy while reducing the toxic side effects.

On the other hand, we collaborated with chemists to develop novel small-molecule compounds against epigenetic enzymes that are often dis-regulated in cancers. We discovered a lead benzamide compound possessing a potent activity against class I histone deacetylases (HDACs) and exhibiting strong cancer inhibitory activity in vitro and in vivo (Nepali&Chang et al., Eur J Med Chem 2020). The following study further identified the derivative 7 with dual inhibitory activities on HDACs and tubulin polymerization and displaying even more virulent to numerous cancer cell lines including the one with multiple-drug resistance (Singha&Chang et al., Eur J Med Chem 2021). Most recently, we also reported another unique derivative, MPT0L184, which can perturb cell-cycle checkpoints and elicit unscheduled mitosis onset (Chang et al., Biomed Pharmacother 2021). Importantly, these agents showed comparable toxicity in HDAC inhibitor-sensitive and -resistant cells, underscoring the potential to overcome drug resistance.