Pipeline

Target Selection

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.

Beactica’s approach

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.

Improving lives

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). 

Further reading

• Sheng W et al. (2018) LSD1 Ablation stimulates anti-tumor immunity and enables checkpoint blockade. Cell, 174:1–15.
• Qin Y et al. (2018) Inhibition of histone lysine-specific demethylase 1 elicits breast tumor immunity and enhances antitumor efficacy of immune checkpoint blockade. Oncogene, 38:390–405.
• Sehrawat A et al. (2018) LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. PNAS, 115:E4179–E4188.

Selected posters & presentations

• Potentiation of Immunotherapy by LSD1 Modulation, American Association for Cancer Research (AACR) Annual Meeting 2023, Orlando, Florida. Sunday,  16 April, 2023.

Related press releases

• Beactica Therapeutics announces the selection of BEA-17 as a preclinical candidate
• Beactica Therapeutics receives FDA Orphan Drug Designation for BEA-17 for the treatment of glioblastoma

Target Selection

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.

Beactica’s approach

We are utilising our Eclipsor™ platform for targeted protein degradation to develop novel therapeutics for treatment of cancers caused by dysregulation of the Hippo pathway. Lead compound P65-047 is a first-in-class proteolysis-targeting degrader of TEAD transcription factors that outperforms competing palmitoylation inhibitors currently in clinical development.

Improving lives

P65-047 is being developed as stand-alone product in niche cancers and combination therapy for underserved subgroups in common solid tumours.

Further reading

• Calses PC et al. (2019) Hippo pathway in cancer: Aberrant regulation and therapeutic opportunities. Trends in Cancer, 5:297–307. 
• Cunningham R et al. (2022) The Hippo pathway in cancer: YAP/TAZ and TEAD as therapeutic targets in cancer. Clin Sci (Lond), 136:197–222. 
• Pobbati AV et al. (2020) Protein-protein interaction disruptors of the YAP/TAZ-TEAD transcriptional complex. Molecules, 25:6001–6017. 
• Furet P et al. (2022) The first class of small molecules potently disrupting the YAP-TEAD interaction by direct competition. ChemMedChem, e202200303. 

Selected posters & presentations

• Degraders of TEAD Transcription Factors Based on Interface 3 Binders, American Association for Cancer Research (AACR) Annual Meeting 2024, San Diego, California. Sunday,  7 April, 2024.

Related press releases

• Beactica Therapeutics’ TEAD programme selected for late-breaking research presentation at the AACR Annual Meeting 2024 
• Beactica Therapeutics announces collaboration with the National Center for Advancing Translational Sciences at NIH

Key collaborator

Target Selection

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.

Beactica’s approach

We are utilising our expertise in lead generation and Eclipsor™ platform for targeted protein degradation 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 protein degrader that eliminate WRN. 

Improving lives

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.

Further reading

• van Wietmarschen N et al. (2020) Repeat expansions confer WRN dependence in microsatellite-unstable cancers. Nature, 586:292–298.
• Chan EM et al. (2019) WRN helicase is a synthetic lethal target in microsatellite unstable cancers. Nature, 568:551–556.
• Behan FM et al. (2019) Prioritization of cancer therapeutic targets using CRISPR-Cas9 screens. Nature, 568:511–516.
• Kategaya L et al. (2019) Werner Syndrome Helicase Is Required for the Survival of Cancer Cells with Microsatellite Instability. iScience, 13:488–497.

Relateded press releases

• Beactica Therapeutics and University of Dundee announce collaboration to develop WRN inhibitors to target cancer

Key collaborator