Leveraging Innovation To Deliver Precision Medicines

Pipeline

LSD1/HDAC6

Strong scientific and clinical rationale for LSD1/HDAC6 inhibition in haematological and solid tumor

Rationale

  • LSD1 is essential for cancer stem cell survival and maintenance of AML blasts. Both LSD1 and HDAC6 lead to immune suppression through distinct mechanisms
  • Both targets are over-expressed in AML and multiple other cancers
  • LSD1 and HDAC6 are part of co-repressor complexes leading to modulation of cancer-specific genes
  • Current SoCs for AML have a low response rate, limited single agent activity and dose-limiting toxicities
  • Novel therapies targeting multiple pathways are beneficial
  • LSD1 inhibitors alone have shown limited single agent activity
  • Selective inhibition of HDAC6 may reduce the toxicity associated with pan-HDAC inhibitors

The transcriptional corepressor complex CoREST contains multiple proteins including demethylase (LSD1) and deacetylases (HDAC) that regulate the gene expression. Dual LSD1/HDAC6 inhibitor comprehensively blocks the CoREST complex, to show a unique pharmacologic action relative to HDAC or LSD1 inhibitors.

Opportunity

  • Faster clearance, sustained target engagement in malignant cells; minimized systemic toxicity
  • Potential to target MLL rearranged tumors, MDS and other liquid tumors
  • Synergy or overcome resistance when combined with chemotherapy/standard of care
  • Combine with checkpoint inhibitor for solid tumors

Mechanism of Immune Modulation

 

  • HDAC6 inhibition leads to decrease in PD-L1 expression (via IL-4 inhibition)
  • Selective HDAC6i could be used as immunological priming agents to sensitize immunologically “cold” tumors and subsequently improve ongoing immune check-point blockade therapies
  • LSD1 inhibition leads to double-stranded RNA (dsRNA) stress and activation of type 1 interferon, which stimulates anti-tumor T cell immunity and restrains tumor growth.
  • LSD1 depletion enhances tumor immunogenicity and T cell infiltration in poorly immunogenic tumors

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