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. Author manuscript; available in PMC: 2026 Jul 31.
Published in final edited form as: Science. 2026 Jul 9;393(6807):188–194. doi: 10.1126/science.aef5391

Degron-independent recruitment of KAT2A expands the target space of CRBN molecular glues

Samuel Ojeda 1,2,†, Meng Wang 1,2,†, Kheewoong Baek 1,2, Wallace Bourgeois 3, Alba Sommerschield 3, Hong Yue 1,2, Rebecca J Metivier 1,2, Panos Karagiannis 1,2, Talya S Levitz 1,2, Yuan Xiong 1,2, Katherine A Donovan 1,2, Scott A Armstrong 3, Eric S Fischer 1,2,*
PMCID: PMC13423211  NIHMSID: NIHMS2194624  PMID: 42424456

Abstract

Lysine acetyltransferases (KATs) cooperate with oncogenes such as c-Myc, estrogen receptor, and KMT2A-fusions to sustain malignant programs. Targeting of KAT proteins has shown clinical efficacy; however, achieving homolog-selectivity for most KATs remains a major challenge. By extending CRBN-based molecular glues beyond the canonical degron space, we develop an exquisitely selective degrader of KAT2A. Cryo-electron microscopy revealed that CRBN recruits KAT2A independently of a degron; instead, the molecular glue engages a surface-exposed tyrosine, mimicking antibody-like molecular recognition. Selective KAT2A degradation leads to potent ablation of H3K9Ac, antiproliferative effects in acute myeloid leukemia cell lines, and in vivo efficacy in a patient-derived xenograft model, establishing KAT2A as a targetable vulnerability to treat a wide range of malignancies. More generally, degron-independent recruitment extends the CRBN-targetable proteome.

Using small molecules to achieve targeted protein degradation (TPD) of disease-associated proteins is a powerful therapeutic approach to access otherwise unattainable pharmacology, with a growing number of molecules in clinical development (1, 2). Mechanistically, TPD involves hijacking the cellular ubiquitylation machinery by inducing proximity between an E3 ubiquitin ligase and the target protein of interest (POI) to facilitate POI poly-ubiquitylation and its subsequent proteasome-dependent degradation (3). A class of degrader molecules called molecular glues (MGs) is of particular interest because they can target POIs considered undruggable due to absence of well-defined drug-binding pockets, such as transcription factors (4–8). For example, the multiple myeloma drugs lenalidomide and pomalidomide induce degradation of the lymphoid transcription factors IKZF1 and IKZF3 by redirecting the Cullin RING ligase CUL4-RBX1-DDB1-CRBN (CRL4CRBN) (5–8).

Although MGs do not require a drug binding pocket on their POIs, structural studies of ternary complexes involving CRL4CRBN, MG, and the POI identified a common degron motif, termed the β-hairpin G-loop (9–11). Thus, the presence of the G-loop within the POI is considered to be a critical feature of these targets. This realization has facilitated large-scale computational mining of the human proteome for CRBN-compatible G-loop proteins, identifying more than 1,400 new targets for CRBN-redirecting MG development (11, 12). However, the existing druggable target space (13) still only represents about 7% of the human proteome since the majority of proteins, including many of therapeutic interest, lack a G-loop. Therefore, the discovery of CRBN-based MGs that recruit POIs beyond those containing the canonical G-loop has been a major goal in the field. The recent discovery that G3BP2 is recruited independently of a G-loop degron, or structural mimic (14), suggest that such degron-independent recruitment is possible and may be exploited therapeutically (11).

Here, we describe the discovery of a non-degron degrader that induces selective and potent degradation of the lysine acetyl transferase KAT2A, a POI that also lacks a canonical G-loop motif. Members of the lysine acetyl transferase (KAT) family of proteins frequently cooperate with oncogenes such as c-Myc (15, 16), N-Myc (17, 18), estrogen receptor (ER) (19), androgen receptor (AR) (20), and fusion-oncogenes, such as in KMT2A-rearranged acute myeloid leukemia (AML) (21). Efforts to target members of the KAT family, including KAT6A/B, KAT2A/B, and CBP/p300, have led to some clinical success (22–26), but achieving homolog selectivity remains a major challenge. KAT2A has been implicated in regulating and maintaining transcriptional programs in stem and progenitor cells (21). For example, in KMT2A::MLLT3-driven AML, KAT2A has been shown to maintain leukemic transcriptional programs and is required for the preservation of leukemia stem-like progenitor cells (27, 28). Selective targeting of KAT2A could also provide a potential therapeutic route in MDS (Myelodysplastic Syndrome) (25), lymphoblastic leukemia (29), non-small cell lung cancer (NSCLC) (30), prostate adenocarcinoma (31), Burkitt lymphoma (32), and gastric cancer (33).

Discovery of a KAT2A molecular glue degrader.

Initial KAT2A-targeting MG degrader hits were obtained by interrogating our database of target-agnostic global degradation proteomics (34, 35) and immunoprecipitation mass spectrometry (IP-MS) (12), which contains thousands of datapoints for heterobifunctional and MG degraders. We identified compound (1) as a strong degrader of KAT2A (Fig. 1A–B, fig. S1A). 1 was initially synthesized as part of a previous campaign to derivatize CRBN ligands based on a lenalidomide core (36). 1 was the only compound across the entire database to induce degradation of KAT2A (fig. S1A, B). To validate our hit, we performed IP-MS experiments with recombinant CRBN as bait in Kelly cell lysates, as previously described (12), demonstrating potent enrichment of KAT2A in the presence of 1, as well as undesired activity against GSPT1 (Fig. 1C). We next orthogonally confirmed dose-dependent KAT2A degradation by western blot, and demonstrated that this degradation can be rescued by pre-treatment with a UBA3/NAE1 inhibitor, MLN4924 (37), a proteasome inhibitor, bortezomib (38), and a competing CRBN ligand, pomalidomide (7) (Fig. 1D). 1 does not display any degradation activity against KAT2B, a close homolog of KAT2A (Fig. 1D). Together, these data confirm that 1 mediates KAT2A degradation in a CRBN and proteasome-dependent manner.

Figure 1. Discovery of a KAT2A molecular glue degrader.

Figure 1.

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(A) Schematic demonstrating the generation of KAT2A degradation values from the HT-degradomics CRBN-MG screen. (B) Scatterplot depicting relative protein abundance following 6-hour treatment of Kelly cells with 1 μM compound (1), n=2, vs. DMSO, n=4. Log2 FC shown on the y-axis and negative log10 P-value on the x-axis. (C) Ranked protein enrichment plot of relative protein abundance following Flag-CRBN-DDB1ΔB enrichment from in-lysate treatment with 1, n=4, vs DMSO, n=4. (D) Immunoblots of dose-response treatment of 1 in Kelly cells after 6-hour treatment. Degradation rescues performed by pre-treating 1 μM of MLN4924, Bortezomib, or pomalidomide. Protein abundance of KAT2A, KAT2B, GSPT1, and GSPT2 is shown with GAPDH abundance used as a loading control. (E) Immunoblot of in-vitro ubiquitylation assays utilizing purified recombinant proteins for KAT2A full length (KAT2AFL), KAT2A acetyl transferase domain (KAT2AKAT), KAT2A bromodomain (KAT2ABRD), KAT2A N-terminal domain (KAT2ANTD).

To validate KAT2A as a genuine CRBN-dependent neo-substrate, we used an in vitro reconstituted system with recombinant CRL4CRBN E3 ubiquitin ligase and observed compound-dependent ubiquitylation of full-length KAT2A (Fig. 1E, lanes 1-2), unambiguously confirming that 1 acts as a direct molecular glue between CRBN and KAT2A. Based on prior structures and AlphaFold2 (39) predictions, KAT2A lacked a canonical G-loop motif or a similar structure, which suggested a different binding mode. To map which domain of KAT2A is responsible for recruitment to CRBN, we recombinantly expressed and purified the following defined domains of KAT2A: the KAT domain, the Bromodomain (BRD), and the N-terminal domain (NTD) (fig. S1C). In vitro ubiquitylation assays using the individual domains showed that only the N-terminal domain was polyubiquitylated in the presence of 1, suggesting that the recruitment interface is located within the N-terminal domain of KAT2A (KAT2ANTD) (Fig. 1E, lanes 7,8). We also found that 1 does not induce poly-ubiquitylation of the corresponding N-terminal domain of KAT2B (KAT2BNTD), establishing biochemical selectivity of this induced interaction (Fig 1E, lanes 9,10). Taken together, our screen for MG degraders of KAT2A discovered 1, a potent degrader that selectively binds and degrades KAT2A over the closely related KAT2B.

Optimization of potent and selective KAT2A degraders.

To further optimize the KAT2A MG degrader, we focused on improving KAT2A potency and efficacy while dialing out GSPT 1/2 activity. Modeling of GSPT1 recruitment to CRBN by 1, based on a previously published GSPT1-CC855-CRBN (PDB: 5HXB) (40) complex structure, led us to hypothesize that a bulkier replacement of the isopropyl group would be incompatible with GSPT1 recruitment (fig S2A). Thus, we generated a series of molecules replacing the isopropyl with bulky substituents. Assessment of KAT2A and GSPT1 dimerization with CRBN using a Time Resolved-Förster Resonance Energy Transfer (TR-FRET) assay (fig. S2B) demonstrated that a 2-tetrahydropyran (2-THP) group replacing the isopropyl ablates GSPT1 targeting, as exemplified in compound (2) (Fig. 2A, fig. S2B, C), while enhancing KAT2A-CRBN dimerization. Keeping the 2-THP to retain selectivity, we sought to further improve KAT2A activity. Through iterative rounds of medicinal chemistry (see also Supplementary Text), we identified two additional substitutions that resulted in improved KAT2A-CRBN dimerization activity (fig. S2B) while retaining selectivity over GSPT1: replacement of the central pyrimidine with a pyridine (compound (3), fig. S2G–I) and replacing the indane with a 1-tert-butylimidazolidin-2-one group (compound (4), Fig. 2A). Using an endogenous HiBiT-tagged (41) KAT2A reporter cell line to assess the degradation of KAT2A in Kelly cells after a 6-hour treatment, we found that each sequential modification led to improved KAT2A degradation in cells, with 4 displaying the most potent KAT2A degradation in the series (Dmax: 90%, Fig. 2B). By immunoblot, 4 showed potent KAT2A degradation with no GSPT1 or GSPT2 degradation activity up to 1 μM, and negligible KAT2B degradation at doses >250 nM (Fig. 2C). Furthermore, 4 significantly reduced histone H3 lysine 9 acetylation (H3K9Ac), a primary KAT2A acetylation target (42), in a dose-dependent manner in Kelly cells (Fig. 2C). Finally, we validated proteome-wide selectivity by performing both global proteomics (Fig. 2D) and CRBN-IP-based proteomics from Kelly cell lysate (Fig. 2E) and identified KAT2A as the only protein robustly recruited to CRBN and degraded in the presence of 4 (MAGEA10 is a known KAT2A interactor (43)). Together, these data establish 4 as a potent molecular glue degrader of KAT2A, with exquisite selectivity and no observable off-target degradation.

Figure 2. Optimization of potent and selective KAT2A degraders.

Figure 2.

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(A) Compound structures of compound 1 (on the left) and compounds 2-4 (on the right). CRBN binding side of compounds (2–4) cropped out and changes from 1 highlighted. (B) Degradation of endogenous Hibit-KAT2A following dose-response, n=2, of 1 (blue), 2 (green), 3 (purple), and 4 (red). Protein abundance measured by normalized luminescence. (C) Immunoblots of dose-response treatment of 4 in Kelly cells after 6-hour treatment. Degradation rescues performed by pre-treating with 1 μM MLN4924 or Bortezomib. Protein abundance of KAT2A, GSPT1, GSPT2, and KAT2B shown with GAPDH abundance used as a loading control. H3 and H3K9Ac abundance shown after histone extraction protocol. (D) Scatterplot depicting relative protein abundance following 6-hour treatment of Kelly cells with 1 μM 4, n=2, vs. DMSO, n=4. Log2 FC shown on the y-axis and negative log10 P-value on the x-axis. (E) Ranked protein enrichment plot of relative protein abundance following Flag-CRBN-DDB1ΔB enrichment from in-lysate treatment with 4, n=4, vs DMSO, n=4.

KAT2A recruitment to CRBN is degron-independent.

As mentioned above, all CRBN MG-dependent neo-substrates described in the literature, except for the recently discovered G3BP2 (14), feature either a G-loop or a structural mimic of this loop (4, 11), and the absence of such features in KAT2A, along with the scarcity of hits in our database, indicated a recruitment mechanism that does not depend on a canonical degron. To visualize how 4 induces the recruitment of KAT2A to CRBN, we determined a 2.9 Å resolution cryo-EM structure of the DDB1ΔB-CRBN-4-KAT2ANTD ternary complex (Fig. 3, fig. S3). The structure showed clear density for each protein and unambiguous density for 4 at the interface between CRBN and KAT2ANTD (Fig. 3, fig S4A, B, D). The compound-mediated interface between CRBN and KAT2ANTD not only lacks a G-loop structural motif but also does not contain a structural mimic of the canonical motif as seen in VAV1 (11). Instead, 4 recruits KAT2ANTD via a globular helical domain mediated by a solvent-exposed tyrosine interacting with 4. The overall arrangement is stabilized by three distinct interaction sites between KAT2ANTD and CRBN (Fig. 3A–D). At the compound-mediated interface, the bulky hydrophobic groups of 4 wrap around the surface exposed Y200 within an α-helix of KAT2ANTD (Fig. 3A). The second interface, the “Helix interface”, is formed between the end of two α-helixes on KAT2ANTD and the zinc-coordinating region on the C-terminal domain of CRBN (CRBNCTD) (Fig. 3C). The third interface, the “Loop interface”, is formed between F150 on the N-terminal domain loop of CRBN (CRBNNTD) and several residues near the binuclear zinc-coordinating region of KAT2ANTD (Fig. 3D).

Figure 3. Structural and biochemical characterization of the KAT2ANTD-4-CRBN ternary complex.

Figure 3.

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(A) Close-up of the compound 4 induced interface, with compound highlighted in space-filling representation (above). Close-up of KAT2ANTD-4 interactions with significant interacting residues highlighted in space-filling representation (below). (B) Cryo-EM map of the KAT2ANTD-4-CRBN ternary complex. Map obtained from global refinement at a 2.9-Å resolution and sharpened using DeepEMenhancer. (C) Close-up of the CRBNCTD● KAT2ACTD Helix interface highlighting. (D) Close-up of the CRBNNTD-KAT2ANTD Loop interface. (E) TR-FRET KAT2A displacement assay titrating unlabeled protein constructs, n=2, to displace terbium-labeled KAT2ANTD from a 4-induced ternary complex. Normalized 520/490 signal on the Y-axis and log10 of unlabeled construct concentration on the X-axis. Disrupted interface mutants of KAT2A shown in blue (Y200A), yellow (Loop: F109E, F202E, F183A, R206A), and green (Helix: K289A, V285A, R277A). (F) Comparison of sunbstrate-interacting residues on CRBN in various CRBN-MG ternary structures using PDBePISA. KAT2A (PDB: 10DW), IKZF1 (8D7Z)(45), GSPT1 (5HXB)(40), VAV1 (9NFR)(11).

To validate the contribution of these three interfaces to binding, we performed mutational analyses on KAT2ANTD. Using a TR-FRET displacement assay we found that Y200A mutation is sufficient to significantly perturb WT KAT2ANTD recruitment to CRBN (25x IC50 shift; Fig. 3E). Moreover, mutating multiple key residues in the Loop (F109E, F202E, F183A, R206A) and Helix (K289A, V285A, R277A) interfaces, were sufficient to completely ablate recruitment (Fig. 3E). Further validation using in vitro ubiquitylation assays show that the Y200A mutation as well as mutations on the Loop and Helix interfaces are sufficient to disrupt 4 induced KAT2A ubiquitylation (fig. S4F). This suggests that each of the three interaction sites contributes to an avid interface between CRBN and KAT2A and is indispensable for KAT2A recognition, which was underscored by high ternary complex affinity and observable, albeit weak, binding of KAT2A to CRBN in the absence of glue (fig. S4H). As such, although KAT2BNTD has a tyrosine analogous to Y200 in KAT2A, and 71% sequence identity, the extensive nature of interactions that define 4-mediated KAT2A recruitment to CRBN explains the exquisite selectivity for KAT2A over KAT2B.

To compare the KAT2A engagement and interface with CRBN to previously published CRBN-based MG-induced ternary complexes, we then identified interface residues buried by KAT2ANTD on CRBN using PDBePISA (44) (Fig 3F). We found that KAT2ANTD buries a substantial portion of both the CRBNNTD and CRBNCTD, forming a broad PPI that is distinct from the more hotspot-driven interfaces created by the G-loop neo-substrates (e.g., IKZF1(45), GSPT1(40)), the G-loop mimetic (VAV1(11)), and the non-G-loop (G3BP2(14)) (Fig 3F). This large interface is likely necessary to compensate for the lack of extensive primary interactions between the compound/CRBN composite surface and KAT2A. The distinctive nature of the KAT2A binding mode, essentially consisting of a single exposed residue within an α-helix, the extensive protein-protein interaction (PPI) interface area with CRBN supporting this interaction, and the dissimilarity with the canonical IMiD degrons, together suggest a major expansion of the potential target space for CRBN-mediated degradation.

Compound 4 shows antiproliferative activity in AML cell lines.

KAT2A has previously been identified as a potential targetable dependency in AML through functional genomic studies (28, 27, 46). However, in the absence of homolog-selective inhibitors or degraders, selective KAT2A inactivation has not been tested pharmacologically. We therefore set out to characterize KAT2A degradation across a panel of 7 AML cell lines with distinct genetic drivers, selected to represent a range of sensitivity to KAT2A loss as determined by mining DepMap (47, 48). First, we performed viability assays after 9-days of treatment with 4 (Fig. 4A). Four out of the seven cell lines tested (MV4;11 (KMT2A::AFF1), EOL-1 (KMT2A partial tandem duplication), MOLM13 (KMT2A::MLLT3), and Mono-Mac-6 (KMT2A::MLLT3)) were highly sensitive to 4 treatment with <100 nM absolute IC50s, closely matching the DC50 previously established in Kelly cells, while the remaining three (NB-4 (PML::RARA), NOMO (KMT2A::MLLT3), and THP1 (KMT2A::MLLT3)) showed little sensitivity. To exclude the possibility of confounding off-targets specific to those cell lines, we profiled the degradation activity of 4 by global expression proteomics in EOL-1 and MV4;11 after a 6-hour treatment with 1 μM of 4 and found that KAT2A is the only protein substantially degraded in both cell lines (Fig 4B, C), consistent with prior data in Kelly cells. 4 treatment also showed a clear reduction of H3K9Ac in a neddylation- and proteasome-dependent manner in both cell lines (Fig. 4D), suggesting sufficient target degradation to functionally perturb KAT2A activity in AML cells. These results demonstrate that the selective degradation of KAT2A by an MG degrader exhibits context-specific anti-leukemic activity rather than general cytotoxicity.

Figure 4. Compound 4 shows potent antiproliferative effects in pre-clinical AML models.

Figure 4.

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(A) Viability curves of seven AML cell lines after 9-day treatment with 4, n=3 for each cell line. Cells split and re-treated when confluent. CTG used as readout for viability. (B) Scatterplot depicting relative protein abundance following 6-hour treatment of EOL-1 cells with 1 μM 4, n=2, vs. DMSO, n=4. Log2 FC shown on the y-axis and negative log10 P-value on the x-axis. (C) Scatterplot depicting relative protein abundance following 6-hour treatment of MV4;11 cells with 1 μM 4, n=2, vs. DMSO, n=3. Log2 FC shown on the y-axis and negative log10 P-value on the x-axis. (D) Immunoblots of dose-course treatment of4 in EOL-1 (above) and MV4;11 (below) cells after 6-hour treatment. Protein abundance for H3K9Ac and H3 was determined after histone extraction. (D) Schematic of DFAM6855 (KMT2A::MLLT3) PDX survival experiment. Cells were injected into the tail veins of mice at day 0, and mice were randomized into vehicle control, n = 6, and 4, 20 mg/kg q24 hours, n = 6. Treatment initiated on day 14. (E) Kaplan-Meier survival plot of mice in the PDX survival experiment, cohort difference significance: p = 0.0023. (F) Human CD45+ percentage in peripheral blood at different timepoints throughout the survival experiment is displayed, with each circle representing an individual mouse. (G) Immunoblots from PDX xenograft experiment. CD45+ cells were harvested at the end of life for each mouse. KAT2A, GSPT1, GSPT2, and KAT2B shown with β-actin abundance used as a loading control. H3 and H3K9Ac abundance shown after histone extraction protocol.

Compound 4 reduces H3K9Ac and leukemic burden in vivo.

To assess whether the potent anti-proliferative activity of 4 in AML cell lines would translate into activity in vivo, we turned to a patient-derived xenograft (PDX) model. We screened several vehicles to optimize drug levels and conducted in vivo PK studies to establish a dosing regimen. We found subcutaneous dosing of 20 mg/kg to be tolerated and to result in acceptable exposure in peripheral blood (fig. S5A). Additionally, a pharmacodynamics experiment using mice engrafted with MV4;11 cells and treated with a dose range of 4 showed KAT2A degradation and loss of H3K9Ac in harvested CD45+ cells after three doses once-daily 20 mg/kg of 4 (Fig. S5B). To assess in vivo efficacy, the DFAM-68555 (KMT2A::MLLT3 AML) PDX model was injected into the tail veins of immunodeficient mice. Mice were then randomized into two cohorts (n = 6 per cohort) 14 days after tail vein injection (Fig 4E). The cohort randomized to 20 mg/kg/day treatment of 4 showed significantly improved median survival compared to those in the vehicle control cohort (47.5 days versus 36.5 days, p = 0.0023), as well as decreased leukemia burden in peripheral blood at several timepoints (Fig. 4F). Immunoblots in human CD45+ cells harvested from bone marrow samples at the time of death of each mouse in the survival experiment showed potent degradation of KAT2A and loss of global H3K9Ac levels in the 4 treated cohort (Fig. 4G). The mice showed no treatment-related changes in body weight or circulating blood cell counts (fig. S5C, D). We conclude that KAT2A degradation demonstrates anti-leukemia activity in vivo.

Discussion:

Historically, the development of chemical probes and drugs capable of discriminating between homologous members of the KAT family of enzymes (e.g., KAT2A/KAT2B, KAT6A/KAT6B, and CBP/p300) has been exceptionally challenging due to high levels of conservation at the KAT domain catalytic and bromodomain acetyl-lysine binding sites. Thus, all clinical stage KAT inhibitors and degraders function as dual inhibitors of the homolog pairs (49), including a KAT2A/KAT2B targeted PROTAC in development (25) and the KAT6A/KAT6B/KAT7 inhibitors in advanced clinical trials (22, 26). This nonspecificity is thought to lead to toxicity in contexts where the therapeutic benefit does not require inhibition of both proteins. In this study, we present a series of selective CRBN-based KAT2A degraders. The selectivity of our degraders is achieved through a composite surface area comprising both MG-mediated contacts and direct KAT2A-CRBN interfaces. Furthermore, the KAT2A-binding site is located in its non-catalytic NTD, suggesting that MGs that exploit non-catalytic domains of POIs for recruitment may offer improved selectivity.

The recently reported degraders of G3BP2 (14) also lack a canonical degron and, similar to KAT2A, the major interface contacting the MG is a helix without noticeable degron-like features. In contrast to KAT2A, however, the interaction of G3BP2 with CRBN appears more hotspot-driven, engaging a defined interface on the LON domain that the authors describe as mimicking a natural PPI. Recent public disclosures by biotech companies have reported additional non G-loop targets, including CCNE1 (50), ARNT (51), CDK2 (52), ALK (53), and, while details of those recruitment modes have yet to be published, together these results show that the targetable universe of proteins degradable by CRBN-recruiting MGs is not limited to POIs that contain the G-loop degron motif (4), or its structural mimic (11). 4 recruits KAT2A to CRBN via a relatively featureless surface through a single exposed amino acid (Y200) located on a helix, a structural feature without homology to previously reported degrons. Furthermore, the large interface area involves extensive interactions between CRBN-MG and KAT2A, providing measurable affinity of KAT2A-CRBN in the absence of MG (54) and resembling the molecular recognition seen in immunoglobulin (Ig) binding to antigens. Therefore, we propose that CRBN-MG binary complexes should be viewed as key recognition elements reminiscent of the heavy chain complementary-determining region (CDR) 3 of Ig’s (Fig. S4G). In this model, binding of different MGs, not mutations, changes the properties of the binding interface, thereby dictating POI selectivity. Furthermore, additional loops in CRBN (most notably residues 146-153) behave like CDR1 and CDR2 of Ig’s, whereby they accommodate the target while keeping entropic costs in check due to their limited flexibility (Fig. S4G), a feature we also recently observed in the recruitment of ENL by dHTC1 (55) and the same CRBN loop (146-153) also plays a role in G3BP2 recruitment (14). As such, further diversifying the substituents attached to the core glutarimide moiety of CRBN-recruiting MGs is likely to yield potent and selective leads for a diverse range of POIs, including those that lack the G-loop degron. Using this conceptual framework, it is conceivable that one could train predictive models that learn the commonalities of these loop interactions with targets, while treating the glue as a latent variable, to predict probabilities of glueability between ligase:target pairs prior to ligand discovery.

From a translational perspective, the exceptional selectivity of 4 enabled the first pharmacologic testing of selective KAT2A degradation for the treatment of AML. This chemical probe will further allow pharmacologic investigation of KAT2A degradation in other indications with KAT2A dependence, including NSCLC, B-cell lymphomas, colorectal cancer, and neuroblastoma (29, 56, 57). Thus, 4 represents a promising starting point for further therapeutic development.

Supplementary Material

supplementary materials
Data S1
Data S2
Data S3

Materials and Methods

Supplementary Text

Figs. S1 to S5

Table S1, S2

Data S1, S2, S3

References 1-57

Supplementary-only References 58-62

MDAR Reproducibility Checklist

Acknowledgements:

We thank all members of the Fischer and Armstrong labs for advice and support.

Funding:

National Institutes of Health P01CA066996 (ESF, SAA)

National Institutes of Health R01CA262188 (ESF)

National Institutes of Health R01CA214608 (ESF)

National Institutes of Health R01CA218278 (ESF)

Damon Runyon Cancer Research Foundation DRG-2514-24 (KB)

Footnotes

Competing interests:

E.S.F. is a founder, scientific advisory board (SAB) member, and equity holder of Civetta Therapeutics, Proximity Therapeutics, Anvia Therapeutics (also board of directors), Nias Bio, Stelexis Biosciences, and Neomorph (also board of directors). He is an equity holder and SAB member for Photys Therapeutics and Ajax Therapeutics, and an equity holder in Lighthorse Therapeutics and Avilar. E.S.F. is a consultant to Novartis and Deerfield. The Fischer lab receives or has received research funding from Deerfield, Novartis, Ajax, Interline, Bayer, and Astellas. M.W., S.O., Y.X., K.A.D., and E.S.F. are named inventors on patent applications filed by Dana-Farber Cancer Institute related to the compounds described in this work. S.A.A. has been a consultant and/or shareholder for Neomorph, C4 Therapeutics, Accent Therapeutics, Hyku Therapeutics, and Nimbus Therapeutics. S.A.A. has received research support from Janssen and Syndax. K.A.D. receives or has received consulting fees from Kronos Bio and Neomorph Inc. All other authors declare no competing interests.

Data, code, and materials availability:

Cryo-EM maps are available from Electron Microscopy Data Bank with accession code: EMD-75101. The corresponding coordinate file is available from the Protein Data Bank under ID: pdb_000010dw. Mass spectrometry raw data is deposited and made available via the PRIDE archive under accessions: PXD072224, PXD072306, and PXD072361. No new code was generated in this study. Compounds reported in this study can be synthesized according to methods in Data S2. Requests for other materials can be made to the corresponding author.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

supplementary materials
NIHMS2194624-supplement-supplementary_materials.docx (8MB, docx)
Data S1
NIHMS2194624-supplement-Data_S1.xlsx (4.6MB, xlsx)
Data S2
NIHMS2194624-supplement-Data_S2.pdf (786.8KB, pdf)
Data S3
NIHMS2194624-supplement-Data_S3.pdf (14.9MB, pdf)

Data Availability Statement

Cryo-EM maps are available from Electron Microscopy Data Bank with accession code: EMD-75101. The corresponding coordinate file is available from the Protein Data Bank under ID: pdb_000010dw. Mass spectrometry raw data is deposited and made available via the PRIDE archive under accessions: PXD072224, PXD072306, and PXD072361. No new code was generated in this study. Compounds reported in this study can be synthesized according to methods in Data S2. Requests for other materials can be made to the corresponding author.

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