While there are more than 500 kinases encoded within the human genome with over 70 FDA approved small molecule kinase inhibitors, mostly for cancer indications, resistance to first line inhibitors often leads to cancer recurrence and poor prognosis. The development of new drugs that overcome such cancer resistance is still a critical unmet medical need. Applying DEL technology in novel ways, we screened a library of 7 billion compounds and identified best-in-class new small molecule chemical entities (“NCE”) with single nM IC50s targeting key tyrosine kinases, including ABL1 and its clinically important mutants, including ABL1-T315I, BTK, JAK1/2/3, TRKA/B/C, ROS1, and AurkA/B/C.
Targeting Nuclear Receptors
Nuclear receptors can bind ligand, leading to a conformational change, homo- or hetero-dimerization, nuclear translocation and DNA binding. Using DEL technologies to screen a proprietary library of stapled peptides, we have identified high affinity binders of the coactivator binding region of the wild type estrogen receptor, ERα, and its mutant, ERα-Y537S.
Driving Apoptosis of Senescent Cells
DNA damage, oxidative stress or oncogenic mutations can activate nuclear translocation of p53 and p53 interacting proteins (p53IP), helping to tether p53 onto the transcriptional promoter of pro-senescence protein, p21. We are using DEL technology to screen a proprietary stapled peptide library for peptides that can disrupt Foxo4-p53 interaction, a key driver of shepherding cells towards senescence.