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).
- 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’s LSD1 programme has been supported by the Swedish Governmental Agency for Innovation Systems (Vinnova) with multiple grants totalling in excess of USD 1 million.