Towards breakthrough therapeutics in oncology

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)

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.

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.

Investment from Vinnova

Beactica Therapeutics’ LSD1 programme has so far been supported by the Swedish Governmental Agency for Innovation Systems (Vinnova) with four separate grants totalling in excess of USD 1 million.

Werner Syndrome Helicase (WRN)

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 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.

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.

Exploratory Targets

Beactica is continually evaluating new synthetic lethality targets with therapeutic breakthrough potential to add to its pipeline.

Partnered Programmes

Information on partnered programmes and key collaborations can be found under Drug Discovery Partnerships.

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