Novel immunomodulatory drugs and neo-substrates

Abstract

Thalidomide, lenalidomide and pomalidomide are immunomodulatory drugs (IMiDs) effective in the treatment of multiple myeloma, myelodysplastic syndrome (MDS) with deletion of chromosome 5q and other hematological malignancies. Recent studies showed that IMiDs bind to CRBN, a substrate receptor of CRL4 E3 ligase, to induce the ubiquitination and degradation of IKZF1 and IKZF3 in multiple myeloma cells, contributing to their anti-myeloma activity. Similarly, lenalidomide exerts therapeutic efficacy via inducing ubiquitination and degradation of CK1α in MDS with deletion of chromosome 5q. Recently, novel thalidomide analogs have been designed for better clinical efficacy, including CC-122, CC-220 and CC-885. Moreover, a number of neo-substrates of IMiDs have been discovered. Proteolysis-targeting chimeras (PROTACs) as a class of bi-functional molecules are increasingly used as a strategy to target otherwise intractable cellular protein. PROTACs appear to have broad implications for novel therapeutics. In this review, we summarized new generation of immunomodulatory compounds, their potential neo-substrates, and new strategies for the design of novel PROTAC drugs.

Role of Aiolos and Ikaros in the Antitumor and Immunomodulatory Activity of IMiDs in Multiple Myeloma: Better to Lose Than to Find Them

“…On the other hand, identification of Ikaros and Aiolos gene targets is relevant to better delineate the therapeutic effects of IMiDs as well as to design new pharmacologic agents to achieve better efficacy and overcome IMiDs resistance, one of the major complications in MM therapy. In this context, novel thalidomide analogs, named Cereblon E3 ligse Moldulating Drugs (CELMoDs), have been synthesized and are currently in clinical trials both as monotherapy and in combination with other drugs (NCT01421524; NCT02773030; NCT03374085) [ 78 ]. They include avadomide (CC-122), iberdomide (CC-220), CC-885 and CC-92480 [ 79 , 80 , 81 , 82 ].…”

Prey for the Proteasome: Targeted Protein Degradation—A Medicinal Chemist's Perspective

“…While the outlook for the chemical biology side of TPD is highly encouraging it is equally bright for the therapeutic angle targeting untagged proteins. Already in the short period of rationally designing protein degraders, post elucidation of the IMiD mode of action (2010), several CRBN modulators with different selectivity profiles haven been identified and three are currently evaluated in clinical trials . This created an excitement towards the identification of additional molecular glue systems with the first results being reported recently .…”

Immunomodulatory Drugs in Acute Myeloid Leukemia Treatment

“…The effects of the new molecules depend on their binding to CRBN. CC-122 (iberdomide) and CC-220 (avodamide) enhance Aiolos and Ikaros degradation and are under investigation for their possible role in lymphoproliferative and rheumatologic disorders [ 54 ]. CC-885 inhibits cancer growth and it has been tested against different cell lines and AML leukemic blasts isolated from patients samples.…”