ArticleNature chemical biology2023
Acetyl-CoA biosynthesis drives resistance to histone acetyltransferase inhibition.
Article in Nature chemical biology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT04606446 (A PHASE 1/2A DOSE ESCALATION AND EXPANSION STUDY TO EVALUATE SAFETY, TOLERABILITY, PHARMACOKINETIC, PHARMACODYNAMIC, AND ANTI-TUMOR ACTIVITY OF PF-07248144 IN PARTICIPANTS WITH ADVANCED OR METASTATIC SOLID TUMORS), which is not on this map. Cited by 30 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A phase 1/2a dose escalation and expansion study to evaluate safety, tolerability, pharmacokinetic, pharmacodynamic, and anti-tumor activity of pf-07248144 in participants with advanced or metastatic solid tumors
Who cites it
30 citing papers in PubMed, 33 citations in OpenAlex.
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- Understanding the epigenetic regulation of lactylation and aberrant lactate metabolism in cancer: From mechanisms to therapeutic strategies (Review).International journal of oncology · 2026Review
- Advances in Mechanism of Action and Efficacy of CBP/p300 Inhibitors in Different Subtypes of Breast Cancer.Molecules (Basel, Switzerland) · 2026Review
- Protein lactylation in health and diseases: molecular mechanisms, biological significance, and clinical implications.Signal transduction and targeted therapy · 2026Review
- An orally active dual CBP/p300 degrader targets core dependencies of multiple myeloma.Cell reports · 2026Article
- Reprogramming of bacterial virulence by lysine acetylation.Nature communications · 2026Article
- Hallmarks of nuclear metabolism: implications for genome integrity, nuclear signaling, and therapeutic targeting.npj metabolic health and disease · 2026Review
- Lactate and Acidification: Emerging Metabolic Regulators of Osteoarthritis.Current medical science · 2026Review
- A chemical-genetic interaction between PAF1 and ENL/AF9 YEATS inhibition.RSC chemical biology · 2026Article
- Bone marrow stromal cells enhance multiple myeloma cells proliferation through regulating LncRNA OVAAL/ENPP1 axis.Open life sciences · 2026Article
- Lysine Acetyltransferase 6 in Health and Disease.MedComm · 2025Review
- Chromatin Regulatory Targets for Anticancer Therapeutics.Chemical reviews · 2025Review
- Histone modifications in cervical cancer: Epigenetic mechanisms, functions and clinical implications (Review).Oncology reports · 2025Review
- The Fundamental Role of Nutrients for Metabolic Balance and Epigenome Integrity Maintenance.Epigenomes · 2025Review
- Mechanisms of metabolism-coupled protein modifications.Nature chemical biology · 2025Review
- Concurrent inhibition of p300/CBP and FLT3 enhances cytotoxicity and overcomes resistance in acute myeloid leukemia.Acta pharmacologica Sinica · 2025Article
- Augmented Acyl-CoA Biosynthesis Promotes Resistance to TEAD Palmitoylation Site Inhibition.ACS chemical biology · 2025Article
- Targeting lysine acetylation readers and writers.Nature reviews. Drug discovery · 2025Review
- Pyrimidine synthesis enzyme CTP synthetase 1 suppresses antiviral interferon induction by deamidating IRF3.Immunity · 2025Article
- Regulation of Histone Acetylation During Inflammation Resolution.ImmunoTargets and therapy · 2025Article
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Authors and funding
10 authors at 3 institutions in 1 country.
Funding
Abstract
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.