Rothmund-Thomson Syndrome (RTS) is a rare genetic disorder with fewer than 500 cases reported in the literature[1]. Of these cases, 60% are classified as RTS type 2 which is caused by bi-allelic germline mutations of RECQL4 [1-6] – a member of the RecQ family of helicases which play essential roles in the maintenance of genome integrity [7]. For individuals that have RTS type 2, there is a >50,000-fold elevated risk of developing cancer (particularly osteosarcoma) during childhood and adolescence. Previously, we discovered that the loss of KLHDC3, an adaptor of the Cullin2-RING E3 ubiquitin ligase (CRL2) complex that degrades specific protein substrates[8, 9], restored cellular viability and proliferation in the presence of a pathogenic RECQL4 point mutation (PM), without apparent effects on RECQL4 wild-type cells. We think KLHDC3 might be a good target for drug discovery.
A homology model of KLHDC3 was created using the predicted data from AlphaFold. Analysis of this model found 9 potential binding partners, which interacted with KLHDC3 at a sight conserved between mouse and human, but unique to KLHDC3 over other members of the KLHDC family. Utilising this data, I identified druggable pockets in KLHDC3 and conducted a virtual screen for small molecule inhibitors. We purchased 100 inhibitors and are assessing these for binding affinity to human KLHDC3 using Surface Plasmon Resonance. The outcome of this will address the potential of targeted KLHDC3 inhibition as a unique therapeutic strategy for the prevention and treatment of cancers affecting patients with RECQL4 mutation.