IMiDs: well-established therapies for patients with multiple myeloma

Immuno-modulatory drugs (IMiDs) are well-established therapies for patients with multiple
myeloma (MM). IMiDs work by binding to the E3 ligase cereblon and allosterically enabling the degradation of the key myeloma transcription factors IKZF1 (Ikaros) and IKZF3 (Aiolos).

Key downstream targets include the transcription factors IRF4 and MYC. As a ligand for binding to cereblon, IMiDs serve as a common scaffold in the design of targeted protein degraders.

E1A-associated protein p300 (EP300) and CREB-binding protein (CBP) are paralogs possessing histone acetyltransferase (HAT) activity and harbor bromodomains (BRDs) that serve to regulate the HAT activity. EP300 and CBP also function in large protein complexes that regulate the transcription of thousands of genes, including those critical for promoting growth and transformation. Inhibitors of the BRDs of EP300 and CBP are known to reduce the activity of key drivers of MM progression and maintenance, again including IRF4 and MYC.

Opna is developing first-in-class multifunctional degraders that combine an IMiD with EP300/CBP binding ligands

The hypothesis is that a multifunctional chimera will cause degradation of all four key proteins, namely EP300, CBP, IKZF1 and IKZF3, and thus be highly active as a single agent in hematological malignancies such as myeloma and lymphoma.