Discovery and characterization of a selective IKZF2 glue degrader for cancer immunotherapy

Bonazzi, Simone; d’Hennezel, Eva; Beckwith, Rohan E. J.; Xu, Lei; Fazal, Aleem; Magracheva, Anna; Ramesh, Radha; Cernijenko, Artiom; Antonakos, Brandon; Bhang, Hyo-eun C.; García, Roxana; Cobb, Jennifer; Ornelas, Elizabeth; Ma, Xiaolei; Wartchow, Charles; Clifton, M.C.; Forseth, Ry R.; Fortnam, Bethany Hughes; Lu, Hongbo; Csibi, Alfredo; Tullai, Jennifer; Carbonneau, Seth; Thomsen, Noel M.; Larrow, Jay F.; Chie-Leon, B.; Hainzl, Dominik; Gu, Yi; Lu, Darlene; Meyer, Matthew J.; Alexander, Dylan C.; Kinyamu-Akunda, Jacqueline; Sabatos-Peyton, Catherine; Dales, Natalie A.; Zécri, Frédéric; Jain, Rishi K.; Shulok, Janine; Wang, Y. Karen; Briner, Karin; Porter, Jeffery A.; Tallarico, John A.; Engelman, Jeffrey A.; Dranoff, Glenn; Bradner, James E.; Visser, M.; Solomon, Jonathan M.

doi:10.1016/j.chembiol.2023.02.005

Cited by 63 publications

(46 citation statements)

References 59 publications

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“…Diagrams of the modular Cul4-RING complexed with different substrate receptor, substrate adaptor complexes (c) DCAF15-DDB1-DDA1 and (d) CRBN-DDB1, which can facilitate interactions between the substrate and an E2 conjugating enzyme to initiate substrate degradation. Structures of the ternary complexes of CRBN* with a MG and additional neosubstrates IKZF2 ZF2 (PDB 7U8F)41 and GSPT1 (PDB 5HXB)12 are shown in FigureS1.…”

mentioning

confidence: 99%

Oligomeric Remodeling by Molecular Glues Revealed Using Native Mass Spectrometry and Mass Photometry

Huang

Kamadurai²,

Siuti³

et al. 2023

J. Am. Chem. Soc.

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Molecular glues stabilize interactions between E3 ligases and novel substrates to promote substrate degradation, thereby facilitating the inhibition of traditionally "undruggable" protein targets. However, most known molecular glues have been discovered fortuitously or are based on well-established chemical scaffolds. Efficient approaches for discovering and characterizing the effects of molecular glues on protein interactions are required to accelerate the discovery of novel agents. Here, we demonstrate that native mass spectrometry and mass photometry can provide unique insights into the physical mechanism of molecular glues, revealing previously unknown effects of such small molecules on the oligomeric organization of E3 ligases. When compared to well-established solution phase assays, native mass spectrometry provides accurate quantitative descriptions of molecular glue potency and efficacy while also enabling the binding specificity of E3 ligases to be determined in a single, rapid measurement. Such mechanistic insights should accelerate the rational development of molecular glues to afford powerful therapeutic agents.

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confidence: 99%

Oligomeric Remodeling by Molecular Glues Revealed Using Native Mass Spectrometry and Mass Photometry

Huang

Kamadurai²,

Siuti³

et al. 2023

J. Am. Chem. Soc.

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“…A notable exception is the GSPT1 degrader SJ6986, which shows significant selectivity against typical IMiD neosubstrates, though low expression levels of some (e.g., SALL4) in the used cell lines complicate a full selectivity assessment. Novartis has recently disclosed the profile of IKZF2 molecular glue degrader NVS-DKY709, which shows an impressive level of selectivity for IKZF2 over closely related zinc finger transcription factors IKZF1/3 . In addition, DKY709 does not degrade GSPT1 but retains glue degrader activity against SALL4.…”

Section: Quality Criteria For Molecular Degrader Probesmentioning

confidence: 99%

“…Novartis has recently disclosed the profile of IKZF2 molecular glue degrader NVS-DKY709, which shows an impressive level of selectivity for IKZF2 over closely related zinc finger transcription factors IKZF1/3. 84 In addition, DKY709 does not degrade GSPT1 but retains glue degrader activity against SALL4. There may soon be further examples of such highly selective CRBN-hijacking molecular glue degraders resulting from more extensive SAR studies to minimize the intrinsic polypharmacology of this class of molecules.…”

Section: Examples Of High-quality Degrader Probesmentioning

confidence: 99%

Expanding Chemical Probe Space: Quality Criteria for Covalent and Degrader Probes

Hartung

Rudolph²,

Mader

et al. 2023

J. Med. Chem.

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Within druggable target space, new small-molecule modalities, particularly covalent inhibitors and targeted degraders, have expanded the repertoire of medicinal chemists. Molecules with such modes of action have a large potential not only as drugs but also as chemical probes. Criteria have previously been established to describe the potency, selectivity, and properties of smallmolecule probes that are qualified to enable the interrogation and validation of drug targets. These definitions have been tailored to reversibly acting modulators but fall short in their applicability to other modalities. While initial guidelines have been proposed, we delineate here a full set of criteria for the characterization of covalent, irreversible inhibitors as well as heterobifunctional degraders ("proteolysis-targeting chimeras", or PROTACs) and molecular glue degraders. We propose modified potency and selectivity criteria compared to those for reversible inhibitors. We discuss their relevance and highlight examples of suitable probe and pathfinder compounds. ■ SIGNIFICANCE• High-quality chemical probes are important tools which allow generation of robust and reproducible insights into the cellular function of proteins of interest. • Covalently acting small molecules and small-molecule protein degraders extend druggable space beyond that fraction of the proteome which is targetable with reversibly acting ligands. • When applied, the proposed set of quality criteria increases the likelihood that cell biology studies provide robust insights of high basic and translational relevance.

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“…Instead of inhibiting the ligase, IMiD binding was accompanied by a gain-of-function phenotype through a molecular glue MoA leading to the recruitment, ubiquitination and subsequent degradation of Ikaros transcription factors (IKZF) (Krönke et al, 2014;Lu et al, 2014). Key structural insights about the IMiD binding mode and its ability to glue proteins to CRBN (Fischer et al, 2014;Petzold et al, 2016) paved the way for the use of IMiDs, both as handles for PROTACs (Lu et al, 2015;Winter et al, 2015) as well as molecular glues for de novo target proteins (Bonazzi et al, 2023) A common key asset for both classes of TPD molecules are binders to E3 ligases to enable recruitment of de novo substrates. Even though there are ca.…”

Section: Introductionmentioning

confidence: 99%

Reinstating targeted protein degradation with DCAF1 PROTACs in CRBN PROTAC resistant settings

Schröder

Renatus

Liang

et al. 2023

Preprint

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Targeted protein degradation (TPD) of neo-substrates with proteolysis targeting chimeras (PROTACs) or molecular glues has emerged as a key modality in exploring new biology as well as designing new drug candidates where catalytic inhibition is neither efficacious nor an option. TPD is mediated through harnessing E3 ligases and redirecting them to ubiquitinate de novo target proteins for subsequent proteasomal degradation. Until recently, E3 ligase chemical matter available for mediating TPD has been limited to a relatively low number of ligases, considering that over 600 E3 ligases are encoded by the human genome. In addition, the most utilized ligase for TPD approaches, CRBN, has been observed to be downregulated in settings of acquired resistance to immunomodulatory inhibitory drugs (IMiDs). IMiDs are molecular glues that target IKZF transcription factors to CRBN for degradation. Resistance is potentially accelerated by non-essentiality of CRBN for cell viability. Here we investigated if the essential E3 ligase receptor DCAF1 can be harnessed for TPD utilizing a potent, non-covalent DCAF1 binder. We show that this binder, selective for the CRL4DCAF1 E3 ligase complex, can be functionalized into an efficient DCAF1-BRD9 PROTAC. Chemical and genetic rescue experiments confirm specific degradation via the CRL4DCAF1 E3 ligase. We further highlight the versatility of DCAF1 for TPD by developing a DCAF1-dasatininb PROTAC targeting multiple cytosolic and membrane bound tyrosine kinases. We expand these findings towards Brutons tyrosine kinase (BTK) selective PROTACs and through extensive optimization and characterization efforts share key observations that led to a potent and selective DCAF1-BTK PROTAC (DBt-10). Finally, with this PROTAC DBt-10, we show rescue of BTK degradation in a BTK-dependent, CRBN-degradation-resistant cell line and provide a rationale for E3 ligase swap to overcome CRBN mediated resistance.

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Discovery and characterization of a selective IKZF2 glue degrader for cancer immunotherapy

Cited by 63 publications

References 59 publications

Oligomeric Remodeling by Molecular Glues Revealed Using Native Mass Spectrometry and Mass Photometry

Oligomeric Remodeling by Molecular Glues Revealed Using Native Mass Spectrometry and Mass Photometry

Expanding Chemical Probe Space: Quality Criteria for Covalent and Degrader Probes

Reinstating targeted protein degradation with DCAF1 PROTACs in CRBN PROTAC resistant settings

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