Beactica is using its proprietary and world-leading drug discovery platform to build a pipeline of novel and mechanistically defined small molecule therapeutics to address unmet medical needs.
Lysine-specific demethylase 1 (LSD1/KDM1A) is an epigenetic enzyme that regulates expression of large number of target genes and functions as a scaffolding protein that stabilizes transcriptional complexes. Furthermore, it is frequently overexpressed in cancer where it contributes to tumour growth. There is also strong evidence that inhibiting LSD1 function not only suppresses cancer growth, but also promotes anti-tumour immunity. The catalytic LSD1 inhibitors currently in clinical trials target the catalytic binding site on the protein and have a limited anti-cancer effect. Identifying alternative approaches that can also disrupt the scaffolding function of LSD1 is therefore of great importance.
By leveraging a targeted approach, established technology and extensive expertise, we are developing a first-in-class small molecule scaffold inhibitor of the LSD1–CoREST complex. Unlike the catalytic LSD1 inhibitors that have shown limited anti-cancer effect in the clinic, our scaffold inhibitors exert their efficacy by inducing degradation of both LSD1 and its partner protein, CoREST. The lead compound, BEA-17, has been shown to potentiate the efficacy of checkpoint inhibitors in syngeneic models of colon cancer. It also potentiates glioblastoma standard-of-care (radiation + temozolomide) in syngeneic models of glioblastoma. Neither is observed with catalytic LSD1 inhibitors.
Beactica’s scaffold inhibitors of LSD1 have the potential to significantly increase the efficacy of immunomodulating cancer treatments such as checkpoint inhibitors and radiation.
The U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation to BEA-17 for the treatment of glioblastoma (GBM), the most common and aggressive form of brain tumour (read more here).
YAP1 (Yes-associated protein 1) is a coactivator that together with TEAD (TEA Domain) transcription factors play key roles in the Hippo signalling pathway that regulate cell proliferation, apoptosis, and stemness. Dysregulation of the Hippo pathway and subsequent activation of TEAD has been reported in a wide range of cancers such as squamous cell carcinoma, head and neck, gynaecological, and gastrointestinal cancers. TEAD has four paralogs, at least one of which is synthetically lethal (TEAD1) in certain genetic settings. The predominate approach pursued by pharmaceutical companies to silence TEAD is to bind to the lipid pocket thereby preventing the S-palmitoylation required for YAP activation of TEAD.
We are utilising our validated platform and expertise in lead generation to develop novel therapeutics for treatment of cancers caused by dysregulation of the Hippo pathway. Binders to interfaces 2 and 3 of TEADs have been identified and are being developed into proteolysis targeting chimeras (PROTACs) that degrade TEAD. PROTACs will be synthetically lethal for subset of cancers.
Degraders of TEAD have the potential to be subtype specific, and to more efficiently block Hippo signalling compared to lipid pocket binders. This could be of particular benefit to patients with NF2-driven cancers such as mesothelioma.
Werner Syndrome Helicase (WRN) is essential for the survival of cancer cells with microsatellite instability (MSI) making it a promising drug target. MSI is the result of mutations in DNA mismatch repair genes and is prevalent in colorectal, gastric, endometrial, and ovarian cancers. Selective inhibition or degradation of WRN is anticipated to induce synthetic lethality in MSI cancer cells. This approach has been validated by in vitro CRISPR knockout experiments and inducible knockdown xenograft in vivo models. MSI is readily detectable in tumour biopsies which can be used to select patients who are most likely to respond.
We are utilising our validated platform and expertise in lead generation to develop novel therapeutics for treatment of cancers with MSI. Selective binders to dynamic binding pockets of WRN have been identified and are currently being developed into catalytic inhibitors and/or proteolysis targeting chimeras (PROTACs) that degrade WRN. The PROTACs approach include exploiting a novel E3 ligase.
Inhibitors and degraders of WRN have the potential to selectively kill cancer cells with MSI while sparing normal cells, thereby maximising clinical gains while minimising negative side effects.
Beactica is continually evaluating new synthetic lethality targets with therapeutic breakthrough potential to add to its pipeline.
Information on partnered programmes and key collaborations can be found under Drug Discovery Partnerships.
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