Inherited blood cancer predisposition through altered transcription elongation.

Despite advances in defining diverse somatic mutations that cause myeloid malignancies, a significant heritable component for these cancers remains largely unexplained. Here, we perform rare variant association studies in a large population cohort to identify inherited predisposition genes for these blood cancers. CTR9, which encodes a key component of the PAF1 transcription elongation complex, is among the significant genes identified. The risk variants found in the cases cause loss of function and result in a ∼10-fold increased odds of acquiring a myeloid malignancy. Partial CTR9 loss of function expands human hematopoietic stem cells (HSCs) by increased super elongation complex-mediated transcriptional activity, which thereby increases the expression of key regulators of HSC self-renewal. By following up on insights from a human genetic study examining inherited predisposition to the myeloid malignancies, we define a previously unknown antagonistic interaction between the PAF1 and super elongation complexes. These insights could enable targeted approaches for blood cancer prevention.

Redirecting the pioneering function of FOXA1 with covalent small molecules.

Pioneer transcription factors (TFs) bind to and open closed chromatin, facilitating engagement by other regulatory factors involved in gene activation or repression. Chemical probes are lacking for pioneer TFs, which has hindered their mechanistic investigation in cells. Here, we report the chemical proteomic discovery of electrophilic compounds that stereoselectively and site-specifically bind the pioneer TF forkhead box protein A1 (FOXA1) at a cysteine (C258) within the forkhead DNA-binding domain. We show that these covalent ligands react with FOXA1 in a DNA-dependent manner and rapidly remodel its pioneer activity in prostate cancer cells reflected in redistribution of FOXA1 binding across the genome and directionally correlated changes in chromatin accessibility. Motif analysis supports a mechanism where the ligands relax the canonical DNA-binding preference of FOXA1 by strengthening interactions with suboptimal sequences in predicted proximity to C258. Our findings reveal a striking plasticity underpinning the pioneering function of FOXA1 that can be controlled by small molecules.

Acetyl-CoA biosynthesis drives resistance to histone acetyltransferase inhibition.

Histone acetyltransferases (HATs) are implicated as both oncogene and nononcogene dependencies in diverse human cancers. Acetyl-CoA-competitive HAT inhibitors have emerged as potential cancer therapeutics and the first clinical trial for this class of drugs is ongoing (NCT04606446). Despite these developments, the potential mechanisms of therapeutic response and evolved drug resistance remain poorly understood. Having discovered that multiple regulators of de novo coenzyme A (CoA) biosynthesis can modulate sensitivity to CBP/p300 HAT inhibition (PANK3, PANK4 and SLC5A6), we determined that elevated acetyl-CoA concentrations can outcompete drug-target engagement to elicit acquired drug resistance. This not only affects structurally diverse CBP/p300 HAT inhibitors, but also agents related to an investigational KAT6A/B HAT inhibitor that is currently in Phase 1 clinical trials. Altogether, this work uncovers CoA metabolism as an unexpected liability of anticancer HAT inhibitors and will therefore buoy future efforts to optimize the efficacy of this new form of targeted therapy.

Mid-latitude net precipitation decreased with Arctic warming during the Holocene.

The latitudinal temperature gradient between the Equator and the poles influences atmospheric stability, the strength of the jet stream and extratropical cyclones1-3. Recent global warming is weakening the annual surface gradient in the Northern Hemisphere by preferentially warming the high latitudes4; however, the implications of these changes for mid-latitude climate remain uncertain5,6. Here we show that a weaker latitudinal temperature gradient-that is, warming of the Arctic with respect to the Equator-during the early to middle part of the Holocene coincided with substantial decreases in mid-latitude net precipitation (precipitation minus evapotranspiration, at 30° N to 50° N). We quantify the evolution of the gradient and of mid-latitude moisture both in a new compilation of Holocene palaeoclimate records spanning from 10° S to 90° N and in an ensemble of mid-Holocene climate model simulations. The observed pattern is consistent with the hypothesis that a weaker temperature gradient led to weaker mid-latitude westerly flow, weaker cyclones and decreased net terrestrial mid-latitude precipitation. Currently, the northern high latitudes are warming at rates nearly double the global average4, decreasing the Equator-to-pole temperature gradient to values comparable with those in the early to middle Holocene. If the patterns observed during the Holocene hold for current anthropogenically forced warming, the weaker latitudinal temperature gradient will lead to considerable reductions in mid-latitude water resources.

BET Bromodomain Proteins Function as Master Transcription Elongation Factors Independent of CDK9 Recruitment.

Processive elongation of RNA Polymerase II from a proximal promoter paused state is a rate-limiting event in human gene control. A small number of regulatory factors influence transcription elongation on a global scale. Prior research using small-molecule BET bromodomain inhibitors, such as JQ1, linked BRD4 to context-specific elongation at a limited number of genes associated with massive enhancer regions. Here, the mechanistic characterization of an optimized chemical degrader of BET bromodomain proteins, dBET6, led to the unexpected identification of BET proteins as master regulators of global transcription elongation. In contrast to the selective effect of bromodomain inhibition on transcription, BET degradation prompts a collapse of global elongation that phenocopies CDK9 inhibition. Notably, BRD4 loss does not directly affect CDK9 localization. These studies, performed in translational models of T cell leukemia, establish a mechanism-based rationale for the development of BET bromodomain degradation as cancer therapy.

Volume of subcortical brain regions in social anxiety disorder: mega-analytic results from 37 samples in the ENIGMA-Anxiety Working Group.

There is limited convergence in neuroimaging investigations into volumes of subcortical brain regions in social anxiety disorder (SAD). The inconsistent findings may arise from variations in methodological approaches across studies, including sample selection based on age and clinical characteristics. The ENIGMA-Anxiety Working Group initiated a global mega-analysis to determine whether differences in subcortical volumes can be detected in adults and adolescents with SAD relative to healthy controls. Volumetric data from 37 international samples with 1115 SAD patients and 2775 controls were obtained from ENIGMA-standardized protocols for image segmentation and quality assurance. Linear mixed-effects analyses were adjusted for comparisons across seven subcortical regions in each hemisphere using family-wise error (FWE)-correction. Mixed-effects d effect sizes were calculated. In the full sample, SAD patients showed smaller bilateral putamen volume than controls (left: d = -0.077, pFWE = 0.037; right: d = -0.104, pFWE = 0.001), and a significant interaction between SAD and age was found for the left putamen (r = -0.034, pFWE = 0.045). Smaller bilateral putamen volumes (left: d = -0.141, pFWE < 0.001; right: d = -0.158, pFWE < 0.001) and larger bilateral pallidum volumes (left: d = 0.129, pFWE = 0.006; right: d = 0.099, pFWE = 0.046) were detected in adult SAD patients relative to controls, but no volumetric differences were apparent in adolescent SAD patients relative to controls. Comorbid anxiety disorders and age of SAD onset were additional determinants of SAD-related volumetric differences in subcortical regions. To conclude, subtle volumetric alterations in subcortical regions in SAD were detected. Heterogeneity in age and clinical characteristics may partly explain inconsistencies in previous findings. The association between alterations in subcortical volumes and SAD illness progression deserves further investigation, especially from adolescence into adulthood.

SuFEx-based chemical diversification for the systematic discovery of CRBN molecular glues.

Molecular glues are small molecules that stabilize protein-protein interactions, enabling new molecular pharmacologies, such as targeted protein degradation. They offer advantages over proteolysis targeting chimeras (PROTACs), which present challenges associated with the size and properties of heterobifunctional constructions, but glues lack the rational design principles analogous to PROTACs. One notable exception is the ability to alter the structure of Cereblon (CRBN)-based molecular glues and redirect their activity toward new neo-substrate proteins. We took a focused approach toward modifying the CRBN ligand, 5'-amino lenalidomide, to alter its neo-substrate specificity using high-throughput chemical diversification by parallelized sulfur(VI)-fluoride exchange (SuFEx) transformations. We synthesized over 3,000 analogs of 5'-amino lenalidomide using this approach and screened the crude products using a phenotypic screen for cell viability, identifying dozens of analogs with differentiated activity. We characterized four compounds that degrade G-to-S phase transition 1 (GSPT1) protein, providing a proof-of-concept model for SuFEx-based discovery of CRBN molecular glues.

A short ORF-encoded transcriptional regulator.

Recent technological advances have expanded the annotated protein coding content of mammalian genomes, as hundreds of previously unidentified, short open reading frame (ORF)-encoded peptides (SEPs) have now been found to be translated. Although several studies have identified important physiological roles for this emerging protein class, a general method to define their interactomes is lacking. Here, we demonstrate that genetic incorporation of the photo-crosslinking noncanonical amino acid AbK into SEP transgenes allows for the facile identification of SEP cellular interaction partners using affinity-based methods. From a survey of seven SEPs, we report the discovery of short ORF-encoded histone binding protein (SEHBP), a conserved microprotein that interacts with chromatin-associated proteins, localizes to discrete genomic loci, and induces a robust transcriptional program when overexpressed in human cells. This work affords a straightforward method to help define the physiological roles of SEPs and demonstrates its utility by identifying SEHBP as a short ORF-encoded transcription factor.

Transcription control by the ENL YEATS domain in acute leukaemia.

Recurrent chromosomal translocations producing a chimaeric MLL oncogene give rise to a highly aggressive acute leukaemia associated with poor clinical outcome. The preferential involvement of chromatin-associated factors as MLL fusion partners belies a dependency on transcription control. Despite recent progress made in targeting chromatin regulators in cancer, available therapies for this well-characterized disease remain inadequate, prompting the need to identify new targets for therapeutic intervention. Here, using unbiased CRISPR-Cas9 technology to perform a genome-scale loss-of-function screen in an MLL-AF4-positive acute leukaemia cell line, we identify ENL as an unrecognized gene that is specifically required for proliferation in vitro and in vivo. To explain the mechanistic role of ENL in leukaemia pathogenesis and dynamic transcription control, a chemical genetic strategy was developed to achieve targeted protein degradation. Acute loss of ENL suppressed the initiation and elongation of RNA polymerase II at active genes genome-wide, with pronounced effects at genes featuring a disproportionate ENL load. Notably, an intact YEATS chromatin-reader domain was essential for ENL-dependent leukaemic growth. Overall, these findings identify a dependency factor in acute leukaemia and suggest a mechanistic rationale for disrupting the YEATS domain in disease.

ENL links histone acetylation to oncogenic gene expression in acute myeloid leukaemia.

Cancer cells are characterized by aberrant epigenetic landscapes and often exploit chromatin machinery to activate oncogenic gene expression programs. Recognition of modified histones by 'reader' proteins constitutes a key mechanism underlying these processes; therefore, targeting such pathways holds clinical promise, as exemplified by the development of bromodomain and extra-terminal (BET) inhibitors. We recently identified the YEATS domain as an acetyl-lysine-binding module, but its functional importance in human cancer remains unknown. Here we show that the YEATS domain-containing protein ENL, but not its paralogue AF9, is required for disease maintenance in acute myeloid leukaemia. CRISPR-Cas9-mediated depletion of ENL led to anti-leukaemic effects, including increased terminal myeloid differentiation and suppression of leukaemia growth in vitro and in vivo. Biochemical and crystal structural studies and chromatin-immunoprecipitation followed by sequencing analyses revealed that ENL binds to acetylated histone H3, and co-localizes with H3K27ac and H3K9ac on the promoters of actively transcribed genes that are essential for leukaemia. Disrupting the interaction between the YEATS domain and histone acetylation via structure-based mutagenesis reduced the recruitment of RNA polymerase II to ENL-target genes, leading to the suppression of oncogenic gene expression programs. Notably, disrupting the functionality of ENL further sensitized leukaemia cells to BET inhibitors. Together, our data identify ENL as a histone acetylation reader that regulates oncogenic transcriptional programs in acute myeloid leukaemia, and suggest that displacement of ENL from chromatin may be a promising epigenetic therapy, alone or in combination with BET inhibitors, for aggressive leukaemia.

Endocarditis: Who Is Particularly at Risk and Why? Ten Years Analysis of Risk Factors for In-hospital Mortality in Infective Endocarditis.

BACKGROUND: Endocarditis is continuously increasing. Evidence exist that the prognosis is adversely affected by the extent of the disease. We looked at risk factors influencing in-hospital mortality (HM). PATIENTS AND METHODS: Between 2010 and 2019, 484 patients, 338 males (69.8%) with mean age of 66.1 years were operated on because of proven endocarditis. In a retrospective study, a risk factor analysis was performed. RESULTS: Overall HM was 30.17%. Significant influencing factors (odds ratios [ORs] or p-value) for HM were: age (p = 0.004), logistic EuroSCORE (p< 0.001), gender (OR = 1.64), dialysis (OR = 2.64), hepatic insufficiency (OR = 2.17), reoperation (OR = 1.77), previously implanted valve (OR = 1.97), periannular abscess (OR = 9.26), sepsis on admission (OR = 12.88), and number of involved valves (OR = 1.96). Development of a sepsis and HM was significantly lower if Streptococcus mitis was the main pathogen in contrast to other bacteria (p< 0.001). Staphylococcus aureus was significantly more often found in patients with a previously implanted prosthesis (p = 0.03) and in recurrent endocarditis (p = 0.02), while it significantly more often showed peripheral septic emboli than the other pathogens (p< 0.001). CONCLUSION: Endocarditis remains life-threatening. Severe comorbidities adversely affected early outcome, particularly, in presence of periannular abscesses. Patients with suspected endocarditis should be admitted to a specialized heart center as early as possible. Streptococcus mitis appears to be less virulent than S. aureus. Further studies are required to verify these findings.

Brain circuits signaling the absence of emotion in body language.

Adaptive social behavior and mental well-being depend on not only recognizing emotional expressions but also, inferring the absence of emotion. While the neurobiology underwriting the perception of emotions is well studied, the mechanisms for detecting a lack of emotional content in social signals remain largely unknown. Here, using cutting-edge analyses of effective brain connectivity, we uncover the brain networks differentiating neutral and emotional body language. The data indicate greater activation of the right amygdala and midline cerebellar vermis to nonemotional as opposed to emotional body language. Most important, the effective connectivity between the amygdala and insula predicts people's ability to recognize the absence of emotion. These conclusions extend substantially current concepts of emotion perception by suggesting engagement of limbic effective connectivity in recognizing the lack of emotion in body language reading. Furthermore, the outcome may advance the understanding of overly emotional interpretation of social signals in depression or schizophrenia by providing the missing link between body language reading and limbic pathways. The study thus opens an avenue for multidisciplinary research on social cognition and the underlying cerebrocerebellar networks, ranging from animal models to patients with neuropsychiatric conditions.

Personalized neurorehabilitative precision medicine: from data to therapies (MWKNeuroReha) - a multi-centre prospective observational clinical trial to predict long-term outcome of patients with acute motor stroke.

BACKGROUND: Stroke is one of the most frequent diseases, and half of the stroke survivors are left with permanent impairment. Prediction of individual outcome is still difficult. Many but not all patients with stroke improve by approximately 1.7 times the initial impairment, that has been termed proportional recovery rule. The present study aims at identifying factors predicting motor outcome after stroke more accurately than before, and observe associations of rehabilitation treatment with outcome. METHODS: The study is designed as a multi-centre prospective clinical observational trial. An extensive primary data set of clinical, neuroimaging, electrophysiological, and laboratory data will be collected within 96 h of stroke onset from patients with relevant upper extremity deficit, as indexed by a Fugl-Meyer-Upper Extremity (FM-UE) score ≤ 50. At least 200 patients will be recruited. Clinical scores will include the FM-UE score (range 0-66, unimpaired function is indicated by a score of 66), Action Research Arm Test, modified Rankin Scale, Barthel Index and Stroke-Specific Quality of Life Scale. Follow-up clinical scores and applied types and amount of rehabilitation treatment will be documented in the rehabilitation hospitals. Final follow-up clinical scoring will be performed 90 days after the stroke event. The primary endpoint is the change in FM-UE defined as 90 days FM-UE minus initial FM-UE, divided by initial FM-UE impairment. Changes in the other clinical scores serve as secondary endpoints. Machine learning methods will be employed to analyze the data and predict primary and secondary endpoints based on the primary data set and the different rehabilitation treatments. DISCUSSION: If successful, outcome and relation to rehabilitation treatment in patients with acute motor stroke will be predictable more reliably than currently possible, leading to personalized neurorehabilitation. An important regulatory aspect of this trial is the first-time implementation of systematic patient data transfer between emergency and rehabilitation hospitals, which are divided institutions in Germany. TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov ( NCT04688970 ) on 30 December 2020.

Immunosuppressive Agents and Thoracic Aortic Aneurysm: Real Correlation or Mere Coincidence?

BACKGROUND: Atherosclerosis, hypertension, age, and fibrillopathies are well-known risk factors for the development of aortic aneurysm. We discovered that a significant proportion of our patients were previously on chemotherapy treatment or long-term treatment with cytostatic agents or immunosuppressive drugs. Thus, we examined this phenomenon. METHODS: A total of 224 patients with thoracic aorta aneurysm were retrospectively analyzed after aortic surgery from 2006 to 2016. Seventy-three patients received aortic wrapping and 151 patients underwent aortic replacement of which 89 had a valve-carrying conduit and 62 a supracoronary ascending replacement. Aortic morphology was assessed by means of compute tomography scan before and after surgery. Demographic data, risk profile, and postoperative complications were collected. Short- and long-term survival analysis was performed. Statistical analysis was performed with SPSS 19.0. RESULTS: Eighty-eight of 224 patients undergoing aortic surgery because of aortic aneurysm had previously or currently been treated with immunosuppressive agents. Dilatation of the ascending aorta was more pronounced in patients without such therapy. Demographic profile, intraoperative, as well as short- and long-term postoperative results did not differ significantly between both groups. CONCLUSION: The potential effect of immunosuppressant and cytostatic therapies on the development of an aortic aneurysm needs further study. Because of the astoundingly high proportion of these patients being found in an unselected aortic aneurysm cohort with immunosuppressive therapy in the past should be monitored for potential development of aortic aneurysm. If it occurs and requires treatment these patients can fortunately be operated upon with the same short- and long-term outcome than patients without such previous therapy.

Evidence for modulation of EEG microstate sequence by vigilance level.

The momentary global functional state of the brain is reflected in its electric field configuration and cluster analytical approaches have consistently shown four configurations, referred to as EEG microstate classes A to D. Changes in microstate parameters are associated with a number of neuropsychiatric disorders, task performance, and mental state establishing their relevance for cognition. However, the common practice to use eye-closed resting state data to assess the temporal dynamics of microstate parameters might induce systematic confounds related to vigilance levels. Here, we studied the dynamics of microstate parameters in two independent data sets and showed that the parameters of microstates are strongly associated with vigilance level assessed both by EEG power analysis and fMRI global signal. We found that the duration and contribution of microstate class C, as well as transition probabilities towards microstate class C were positively associated with vigilance, whereas the sign was reversed for microstate classes A and B. Furthermore, in looking for the origins of the correspondence between microstates and vigilance level, we found Granger-causal effects of vigilance levels on microstate sequence parameters. Collectively, our findings suggest that duration and occurrence of microstates have a different origin and possibly reflect different physiological processes. Finally, our findings indicate the need for taking vigilance levels into consideration in resting-sate EEG investigations.

Structural and effective brain connectivity underlying biological motion detection.

The perception of actions underwrites a wide range of socio-cognitive functions. Previous neuroimaging and lesion studies identified several components of the brain network for visual biological motion (BM) processing, but interactions among these components and their relationship to behavior remain little understood. Here, using a recently developed integrative analysis of structural and effective connectivity derived from high angular resolution diffusion imaging (HARDI) and functional magnetic resonance imaging (fMRI), we assess the cerebro-cerebellar network for processing of camouflaged point-light BM. Dynamic causal modeling (DCM) informed by probabilistic tractography indicates that the right superior temporal sulcus (STS) serves as an integrator within the temporal module. However, the STS does not appear to be a "gatekeeper" in the functional integration of the occipito-temporal and frontal regions: The fusiform gyrus (FFG) and middle temporal cortex (MTC) are also connected to the right inferior frontal gyrus (IFG) and insula, indicating multiple parallel pathways. BM-specific loops of effective connectivity are seen between the left lateral cerebellar lobule Crus I and right STS, as well as between the left Crus I and right insula. The prevalence of a structural pathway between the FFG and STS is associated with better BM detection. Moreover, a canonical variate analysis shows that the visual sensitivity to BM is best predicted by BM-specific effective connectivity from the FFG to STS and from the IFG, insula, and STS to the early visual cortex. Overall, the study characterizes the architecture of the cerebro-cerebellar network for BM processing and offers prospects for assessing the social brain.

Are you laughing at me? Neural correlates of social intent attribution to auditory and visual laughter.

Laughter is a multifaceted signal, which can convey social acceptance facilitating social bonding as well as social rejection inflicting social pain. In the current study, we addressed the neural correlates of social intent attribution to auditory or visual laughter within an fMRI study to identify brain areas showing linear increases of activation with social intent ratings. Negative social intent attributions were associated with activation increases within the medial prefrontal cortex/anterior cingulate cortex (mPFC/ACC). Interestingly, negative social intent attributions of auditory laughter were represented more rostral than visual laughter within this area. Our findings corroborate the role of the mPFC/ACC as key node for processing "social pain" with distinct modality-specific subregions. Other brain areas that showed an increase of activation included bilateral inferior frontal gyrus and right superior/middle temporal gyrus (STG/MTG) for visually presented laughter and bilateral STG for auditory presented laughter with no overlap across modalities. Similarly, positive social intent attributions were linked to hemodynamic responses within the right inferior parietal lobe and right middle frontal gyrus, but there was no overlap of activity for visual and auditory laughter. Our findings demonstrate that social intent attribution to auditory and visual laughter is located in neighboring, but spatially distinct neural structures.

Functional TRIM24 degrader via conjugation of ineffectual bromodomain and VHL ligands.

The addressable pocket of a protein is often not functionally relevant in disease. This is true for the multidomain, bromodomain-containing transcriptional regulator TRIM24. TRIM24 has been posited as a dependency in numerous cancers, yet potent and selective ligands for the TRIM24 bromodomain do not exert effective anti-proliferative responses. We therefore repositioned these probes as targeting features for heterobifunctional protein degraders. Recruitment of the VHL E3 ubiquitin ligase by dTRIM24 elicits potent and selective degradation of TRIM24. Using dTRIM24 to probe TRIM24 function, we characterize the dynamic genome-wide consequences of TRIM24 loss on chromatin localization and gene control. Further, we identify TRIM24 as a novel dependency in acute leukemia. Pairwise study of TRIM24 degradation versus bromodomain inhibition reveals enhanced anti-proliferative response from degradation. We offer dTRIM24 as a chemical probe of an emerging cancer dependency, and establish a path forward for numerous selective yet ineffectual ligands for proteins of therapeutic interest.

The dTAG system for immediate and target-specific protein degradation.

Dissection of complex biological systems requires target-specific control of the function or abundance of proteins. Genetic perturbations are limited by off-target effects, multicomponent complexity, and irreversibility. Most limiting is the requisite delay between modulation to experimental measurement. To enable the immediate and selective control of single protein abundance, we created a chemical biology system that leverages the potency of cell-permeable heterobifunctional degraders. The dTAG system pairs a novel degrader of FKBP12F36V with expression of FKBP12F36V in-frame with a protein of interest. By transgene expression or CRISPR-mediated locus-specific knock-in, we exemplify a generalizable strategy to study the immediate consequence of protein loss. Using dTAG, we observe an unexpected superior antiproliferative effect of pan-BET bromodomain degradation over selective BRD4 degradation, characterize immediate effects of KRASG12V loss on proteomic signaling, and demonstrate rapid degradation in vivo. This technology platform will confer kinetic resolution to biological investigation and provide target validation in the context of drug discovery.

Pharmacological perturbation of CDK9 using selective CDK9 inhibition or degradation.

Cyclin-dependent kinase 9 (CDK9), an important regulator of transcriptional elongation, is a promising target for cancer therapy, particularly for cancers driven by transcriptional dysregulation. We characterized NVP-2, a selective ATP-competitive CDK9 inhibitor, and THAL-SNS-032, a selective CDK9 degrader consisting of a CDK-binding SNS-032 ligand linked to a thalidomide derivative that binds the E3 ubiquitin ligase Cereblon (CRBN). To our surprise, THAL-SNS-032 induced rapid degradation of CDK9 without affecting the levels of other SNS-032 targets. Moreover, the transcriptional changes elicited by THAL-SNS-032 were more like those caused by NVP-2 than those induced by SNS-032. Notably, compound washout did not significantly reduce levels of THAL-SNS-032-induced apoptosis, suggesting that CDK9 degradation had prolonged cytotoxic effects compared with CDK9 inhibition. Thus, our findings suggest that thalidomide conjugation represents a promising strategy for converting multi-targeted inhibitors into selective degraders and reveal that kinase degradation can induce distinct pharmacological effects compared with inhibition.