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
 

Publications

1. Novel dual LSD1/HDAC6 inhibitors for the treatment of multiple myeloma.

Naveen Sadhu M, Sivanandhan D, Gajendran C, Tantry S, Dewang P, Murugan K, Chickamunivenkatappa S, Zainuddin M, Nair S, Vaithilingam K, Rajagopal S. Bioorg Med Chem Lett. 2020 Dec 24;34:127763.

 

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