IKZF2

In a scientific breakthrough that aids our understanding of the internal wiring of immune cells, researchers have cracked the code behind IKAROS, an essential protein for immune cell development and protection against pathogens and cancer. This disruptive research is poised to reshape our comprehension of gene control networks and its impact on everything from eye color to cancer susceptibility and design of novel therapies. In a scientific breakthrough that aids our understanding of the internal wiring of immune cells, researchers at Monash University in Australia have cracked the code behind IKAROS, an essential protein for immune cell development and protection against pathogens and cancer. This disruptive research, led by the eminent Professor Nicholas Huntington of Monash University’s Biomedicine Discovery Institute, is poised to reshape our comprehension of gene control networks and its impact on everything from eye colour to cancer susceptibility and design of novel therapies. The study, published in Nature Immunology, promises pivotal insights into the mechanisms safeguarding us against infections and cancers. When the transcription factor Ikaros/Ikzf1 was deliberately obstructed, be it in preclinical models or humans, the once-mighty activity of Natural Killer (NK) cells, our immune system's frontline warriors, plummeted. Loss of this transcription factor in NK cells resulted in wide-spread dysregulation of NK cell development and function, preventing their ability to recognize and kill virus-infected cells and clear metastatic tumour cells from circulation. Aiolos/Ikzf3 and Helios/Ikzf2, related family member were found to partial compensate for the loss of Ikaros, as such when multiple IKZF-family members were inhibited, NK cells underwent rapidly death. Mechanistically, Aiolos and Ikaros were found to directly bind and activate most members of the JUN/FOS family, transcription factors known for their essential roles in human embryo development and tissue function. This discovery opens the door to the prospect of potential novel cancer therapeutics. NK cells, our first line of defence against pathogens and internal threats like cancers, could be fortified by therapies enhancing their killing prowess by targeting IKAROS and JUN/FOS biology. Professor Huntington notes that drugs targeting IKAROS/AIOLOS have already received approval from the US Food and Drug Administration (FDA) and local Therapeutic Goods Administration (TGA) for the treatment of B cell malignancy “but until now we haven’t understood how these drugs work, armed with this new information it could be possible to develop novel drugs targeting these complexes which may offer differentiated pharmacology and therapeutic index for treating disease,” he said. Importantly on this front, Professor Huntington’s team were able to show that IKAROS had a conserved role in healthy B cells and thus potentially B cell cancers.

SAN DIEGO, Dec. 12, 2023 /PRNewswire/ -- Plexium, Inc. (Plexium), a leading next-generation targeted protein degradation company, today reported that the first subjects have been dosed in a Phase 1 clinical study of orally administered PLX-4545, a potent and selective molecular glue degrader of IKZF2, a classically undruggable transcription factor also known as Helios. "We are very pleased to have dosed the first subjects in the Phase 1 study with PLX-4545, advancing Plexium into a clinical stage company," said Mike Grey, Executive Chairman of Plexium. "Initiation of this study represents an important milestone for Plexium, as PLX-4545 is our first small molecule degrader program stemming from our proprietary drug discovery platform to enter human studies. In addition, we continue to discover potent and selective protein degraders of important cancer targets, such as SMARCA2, CDK2 and CRaf, and we look forward to progressing one or more of these programs into development in 2024." The randomized, double-blind, placebo-controlled, single- and multiple-ascending dose Phase 1 clinical study is designed to primarily assess the safety and tolerability profile of orally administered PLX-4545, as well as measure pharmacokinetics and pharmacodynamics to identify a pharmacologically effective dose. "While checkpoint inhibitors have demonstrated broad clinical activity in several tumor types, many cancer patients are unresponsive to therapy, often due to immune suppression within the tumor stroma," said Simon Bailey, Ph.D., Executive Vice President, Drug Discovery at Plexium. "The immune transcription factor IKZF2 is a marker of highly suppressive regulatory T cells, and we have shown that potent and selective degradation of IKZF2 results in the conversion of Tregs into effector-like T cells. We have also shown that oral administration of PLX-4545 in preclinical in vivo cancer models has demonstrated promising efficacy, an effect that is even more pronounced when PLX-4545 is co-administered with a checkpoint inhibitor." "Data from this initial study will provide a strong foundation for subsequent clinical studies to evaluate PLX-4545 in cancer patients with tumors that are refractory to checkpoint inhibitors, both as a single agent and in combination with a checkpoint inhibitor, an area of high unmet need," continued Dr. Bailey. Plexium expects to announce results from the PLX-4545 Phase 1 study in the second half of 2024. About PLX-4545 PLX-4545 is a potent, selective and orally bioavailable molecular glue degrader of IKZF2, designed to destabilize highly suppressive regulatory T cells (Tregs). PLX-4545 delivers rapid, deep and selective degradation of IKZF2 resulting in destabilization of Tregs in vitro and in vivo. In preclinical studies, PLX-4545 has demonstrated single agent anti-tumor activity in vivo comparable to pembrolizumab and increased efficacy in combination. To learn more about the PLX-4545 clinical trial, visit (Trial registration #ACTRN12623001265662). About Plexium Inc. Plexium Inc. is the premier, next-generation Targeted Protein Degradation (TPD) company seeking to discover monovalent direct degraders and molecular glues that will address difficult to drug targets for the treatment of cancer. The company's proprietary drug discovery platform is designed to identify novel small molecules that induce selective degradation of pathogenic proteins through E3 ligase mediated proteasomal degradation. Plexium is advancing a pipeline of novel targeted monovalent direct degraders and molecular glues for the treatment of cancer, and has also entered into a strategic collaboration with AbbVie to expand the potential of TPD to neurodegenerative diseases. For more information, visit and engage with us on LinkedIn. Plexium Investor and Media Contact: Amy Conrad Juniper Point [email protected] 858-366-3243 SOURCE Plexium

PVTX-321 and PVTX-405 Achieve Development Candidate NominationNEW YORK, March 14, 2023 (GLOBE NEWSWIRE) -- Proteovant Therapeutics, a Roivant Sciences (Nasdaq: ROIV) company leveraging the process of protein degradation to discover and develop transformative medicines for the treatment of patients with life-altering diseases, today announced it will present data on PVTX-321, an estrogen receptor degrader, at the Protein Degradation & Targeting Undruggables Congress USA, March 15-16 in Boston and on PVTX-405, an IKZF2 molecular glue, at the Targeted Protein Degradation Europe Conference, March 28-30 in London. Targeted protein degradation harnesses the body’s natural protein disposal system and offers the potential to develop new medicines targeting historically difficult-to-drug proteins that play an important role in causing serious diseases. Proteovant Therapeutics is discovering and developing best-in-class and first-in-class degraders that can engage previously undruggable targets. “We are advancing a robust pipeline of heterobifunctional degraders and molecular glues that span a range of novel molecular targets, which are implicated in disorders where new medicines are needed,” said Drew Fromkin, CEO, Proteovant Therapeutics. “PVTX-321, our degrader targeting the estrogen receptor, is highly potent and demonstrates impressive, dose dependent tumor growth inhibition and shrinkage in preclinical models. In addition, PVTX-405 has best-in-class potential with robust IKZF2 degradation in vivo. We are enthusiastic about the progress being made across our degrader pipeline and molecular glue platform initiatives.” Presentation at Protein Degradation & Targeting Undruggables Congress USA Title: Discovery and Characterization of an Estrogen Receptor Heterobifunctional Degrader with Best In-Class Potential Session Time: 12:00-12:25 p.m. EDT on March 15, 2023Presenter: Courtney Havens, Director, Biology, Proteovant Therapeutics Presentation at Targeted Protein Degradation Europe Conference Title: Discovery and Characterization of an IKZF2 Selective Molecular Glue Degrader with Best In-Class Potential Session Time: 4:30 p.m. BST on March 29, 2023Presenter: Harshil Dhruv, Associate Director, Biology, Proteovant Therapeutics Following the presentations at each event, materials will be made available online here. About Proteovant TherapeuticsProteovant Therapeutics exploits the ubiquitin-protease system (UPS) to discover and develop transformative medicines for the treatment of patients with life-altering diseases. Protein degradation harnesses the human body’s innate cellular machinery by way of the UPS to identify and mark disease causing proteins for destruction. This promising approach provides the opportunity to target proteins of interest, many of which were previously considered undruggable. Proteovant integrates its degrader drug hunting expertise, MOPED™ molecular glue screening platform, and external partnerships to advance novel protein degraders across a range of therapeutic areas. Founding investors include Roivant Sciences (Nasdaq: ROIV) and SK Inc. Visit www.proteovant.com and follow us on LinkedIn.Media ContactLiz BotenLiz.Boten@canalecomm.com Evoke Canale for Proteovant Therapeutics