Equipping Faith-Based Communities for Cancer Support Ministry: A Pilot Study of Cancer Support Training for Members of African-American Churches in the USA.

Church-academic partnerships focused on cancer, generally target cancer screening and prevention, with few focusing explicitly on cancer survivors. With the population of cancer survivors steadily increasing, highlighting the value of faith-based cancer support ministry is paramount. However, many churches may not have the resources to integrate relevant cancer support ministry and may need to identify ways to reach cancer survivors. We piloted cancer support training to help church members to start a cancer support ministry with African-American churches in Milwaukee, WI. We sought to measure the feasibility of a two-day training workshop to build the capacity of churches through recruiting and training church members on how to foster social support and to disseminate cancer information and resources throughout their churches. Our study was guided by the social networks and social support framework, which we applied to cancer survivorship. Our study supports the feasibility of engaging churches in a virtual training to support the development of cancer support ministries to address the needs of African-American cancer survivors. Based on our recruitment success, workshop attendance, evaluation and retention, our results suggest that a two-day workshop was successful in facilitating the initiation of cancer support ministries within African-American churches.

Discovery of a highly potent, selective, orally bioavailable inhibitor of KAT6A/B histone acetyltransferases with efficacy against KAT6A-high ER+ breast cancer.

KAT6A, and its paralog KAT6B, are histone lysine acetyltransferases (HAT) that acetylate histone H3K23 and exert an oncogenic role in several tumor types including breast cancer where KAT6A is frequently amplified/overexpressed. However, pharmacologic targeting of KAT6A to achieve therapeutic benefit has been a challenge. Here we describe identification of a highly potent, selective, and orally bioavailable KAT6A/KAT6B inhibitor CTx-648 (PF-9363), derived from a benzisoxazole series, which demonstrates anti-tumor activity in correlation with H3K23Ac inhibition in KAT6A over-expressing breast cancer. Transcriptional and epigenetic profiling studies show reduced RNA Pol II binding and downregulation of genes involved in estrogen signaling, cell cycle, Myc and stem cell pathways associated with CTx-648 anti-tumor activity in ER-positive (ER+) breast cancer. CTx-648 treatment leads to potent tumor growth inhibition in ER+ breast cancer in vivo models, including models refractory to endocrine therapy, highlighting the potential for targeting KAT6A in ER+ breast cancer.

Designing a Dyad-Based Digital Health Intervention to Reduce Sedentary Time in Black Breast Cancer Survivors and Their First-degree Relatives: Human-Centered Design Study.

BACKGROUND: Breast cancer, the most commonly diagnosed cancer and second leading cause of cancer-related death in women in the United States, disproportionately affects women from minoritized or low socioeconomic backgrounds. The average woman has an approximately 12% lifetime risk of developing breast cancer. Lifetime risk nearly doubles if a woman has a first-degree relative with breast cancer, and the risk increases as multiple family members are affected. Decreasing sedentary behaviors through moving more and sitting less reduces breast cancer risk and improves outcomes for cancer survivors and healthy adults. Digital health solutions, such as mobile apps that are culturally appropriate, designed with input from the target audience, and include social support, are effective at improving health behaviors. OBJECTIVE: This study aimed to develop and evaluate the usability and acceptability of a prototype app designed with a human-centered approach to promote moving more and sitting less in Black breast cancer survivors and their first-degree relatives (parent, child, or sibling). METHODS: This 3-phase study consisted of app development, user testing, and evaluation of user engagement and usability. Key community stakeholders were engaged in the first 2 (qualitative) phases to provide input into developing the prototype app (MoveTogether). After development and user testing, a usability pilot was conducted. Participants were adult breast cancer survivors who identified as Black and agreed to participate with a relative. Participants used the app and a step-tracking watch for 4 weeks. App components included goal setting and reporting, reminders, dyad messaging, and educational resources. Usability and acceptability were assessed with a questionnaire that included the System Usability Scale (SUS) and semistructured interviews. Data were analyzed with descriptive statistics and content analysis. RESULTS: Participants in the usability pilot (n=10) were aged 30 to 50 years (6/10, 60%), not married (8/10, 80%), and college graduates (5/10, 50%). The app was used on average 20.2 (SD 8.9) out of 28 days-SUS score of 72 (range 55-95)-and 70% (7/10) agreed that the app was acceptable, helpful, and gave them new ideas. Additionally, 90% (9/10) found the dyad component helpful and would recommend the app to friends. Qualitative findings suggest that the goal-setting feature was helpful and that the dyad partner (buddy) provided accountability. Participants were neutral regarding the cultural appropriateness of the app. CONCLUSIONS: The MoveTogether app and related components were acceptable for promoting moving more in dyads of breast cancer survivors and their first-degree relatives. The human-centered approach, which involved engaging community members in the development, is a model for future technology development work. Future work should be done to further develop the intervention based on the findings and then test its efficacy to improve sedentary behavior while considering culturally informed strategies for adoption and implementation within the community. TRIAL REGISTRATION: ClinicalTrials.gov NCT05011279; https://clinicaltrials.gov/ct2/show/NCT05011279.

Increases in Circulating and Fecal Butyrate are Associated With Reduced Blood Pressure and Hypertension: Results From the SPIRIT Trial.

Background Short chain fatty acids (SCFAs) are microbially derived end products of dietary fiber fermentation. The SCFA butyrate reduces blood pressure (BP) in mouse models. The association of SCFAs, including butyrate, with BP in humans is unclear, due in part to predominantly cross-sectional analyses and different biospecimens (blood versus fecal) for SCFA measurement. Longitudinal studies including both circulating and fecal SCFAs are lacking. Methods and Results We leveraged existing data from the SPIRIT (Survivorship Promotion In Reducing IGF-1 Trial), which randomized 121 adult cancer survivors with overweight/obesity to a behavioral weight-loss intervention, metformin, or self-directed weight-loss. Of participants with baseline serum and fecal SCFAs measured (n=111), a subset had serum (n=93) and fecal (n=89) SCFA measurements 12 months later. We used Poisson regression with robust error variance to estimate baseline associations of SCFAs with hypertension, and we assessed the percent change in SCFAs from baseline with corresponding 12-month changes in BP using multiple linear regression. Baseline fecal butyrate was inversely associated with prevalent hypertension (standardized PR [95%CI]: 0.71 [0.54, 0.92]). A 10% increase in fecal butyrate from baseline was associated with decreased systolic BP (ß [95%CI]: -0.56 [-1.01, -0.10] mm Hg), and a 10% increase in serum butyrate was associated with decreased systolic (ß [95%CI]: -1.39 [-2.15, -0.63] mm Hg) and diastolic (ß [95%CI]: -0.55 [-1.03, -0.08] mm Hg) BPs. Butyrate associations with systolic BP were linear and not modified by sex, race, or intervention arm. Conclusions Increased serum or fecal butyrate is associated with lowered BP. Butyrate may be a target for SCFA-centered BP-lowering interventions. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02431676.

Mapping the Lay of the Land: Using Interactive Network Analytic Tools for Collaboration in Rural Cancer Prevention and Control.

BACKGROUND: Cancer mortality rates in the United States are higher in rural than urban areas, especially for colorectal cancer. Modifiable cancer risks (e.g., tobacco use, obesity) are more prevalent among U.S. rural than urban residents. Social network analyses are common, yet rural informal collaborative networks for cancer prevention and control and practitioner uses of network findings are less well understood. METHODS: In five service areas in rural Missouri and Illinois, we conducted a network survey of informal multisector networks among agencies that address cancer risk (N = 152 individuals). The survey asked about contact, collaborative activities, and referrals. We calculated descriptive network statistics and disseminated network visualizations with rural agencies through infographics and interactive Network Navigator platforms. We also collected feedback on uses of network findings from agency staff (N = 14). RESULTS: Service areas had more connections (average degree) for exchanging information than for more time-intensive collaborative activities of co-developing and sustaining ongoing services and programs, and co-developing and sharing resources. On average, collaborative activities were not dependent on just a few agencies to bridge gaps to hold networks together. Users found the network images and information useful for identifying gaps, planning which relationships to establish or enhance to strengthen certain collaborative activities and cross-referrals, and showing network strengths to current and potential funders. CONCLUSIONS: Rural informal cancer prevention and control networks in this study are highly connected and largely decentralized. IMPACT: Disseminating network findings help ensure usefulness to rural health and social service practitioners who address cancer risks.

Approaches for Measuring Inclusive Demographics Across Youth Enjoy Science Cancer Research Training Programs.

The National Cancer Institute's (NCI) Youth Enjoy Science Program (YES) funds initiatives to support the cancer research training and career ambitions of middle school through undergraduate students from populations underrepresented in the biomedical sciences. The program has funded 16 institutions nationally as of January 2022. Given the program's focus on increasing diversity within the cancer research workforce, demographic characteristics of YES trainees provide essential information about the populations being served and program effectiveness. Six programs formed an interest group focused on trainee demographics and surveyed all YES grantees about their demographic data practices. Fifteen programs (94%) completed the survey. Survey data were analyzed through descriptive statistics and thematic coding. Findings revealed considerable variability in programs' approach to demographic data, including which demographics were measured, how they were operationalized, and when and how the data were collected. Half of YES programs (53%) could report underrepresented populations in biomedical research among trainees using consistent definitions. Most programs described efforts to improve their demographic data practices; however, challenges remained for the vast majority. In consideration of these findings, we offer recommendations for inclusive demographic data practices to better define and retain underrepresented populations in biomedical sciences.

Nuclear Transport Factor 2 (NTF2) suppresses WM983B metastatic melanoma by modifying cell migration, metastasis, and gene expression.

While changes in nuclear structure and organization are frequently observed in cancer cells, relatively little is known about how nuclear architecture impacts cancer progression and pathology. To begin to address this question, we studied Nuclear Transport Factor 2 (NTF2) because its levels decrease during melanoma progression. We show that increasing NTF2 expression in WM983B metastatic melanoma cells reduces cell proliferation and motility while increasing apoptosis. We also demonstrate that increasing NTF2 expression in these cells significantly inhibits metastasis and prolongs survival of mice. NTF2 levels affect the expression and nuclear positioning of a number of genes associated with cell proliferation and migration, and increasing NTF2 expression leads to changes in nuclear size, nuclear lamin A levels, and chromatin organization. Thus, ectopic expression of NTF2 in WM983B metastatic melanoma abrogates phenotypes associated with advanced stage cancer both in vitro and in vivo, concomitantly altering nuclear and chromatin structure and generating a gene expression profile with characteristics of primary melanoma. We propose that NTF2 is a melanoma tumor suppressor and could be a novel therapeutic target to improve health outcomes of melanoma patients.

Effects of Behavioral Weight Loss and Metformin on IGFs in Cancer Survivors: A Randomized Trial.

CONTEXT: Higher levels of insulin-like growth factor-1 (IGF-1) are associated with increased risk of cancers and higher mortality. Therapies that reduce IGF-1 have considerable appeal as means to prevent recurrence. DESIGN: Randomized, 3-parallel-arm controlled clinical trial. INTERVENTIONS AND OUTCOMES: Cancer survivors with overweight or obesity were randomized to (1) self-directed weight loss (comparison), (2) coach-directed weight loss, or (3) metformin treatment. Main outcomes were changes in IGF-1 and IGF-1:IGFBP3 molar ratio at 6 months. The trial duration was 12 months. RESULTS: Of the 121 randomized participants, 79% were women, 46% were African Americans, and the mean age was 60 years. At baseline, the average body mass index was 35 kg/m2; mean IGF-1 was 72.9 (SD, 21.7) ng/mL; and mean IGF1:IGFBP3 molar ratio was 0.17 (SD, 0.05). At 6 months, weight changes were -1.0% (P = 0.07), -4.2% (P < 0.0001), and -2.8% (P < 0.0001) in self-directed, coach-directed, and metformin groups, respectively. Compared with the self-directed group, participants in metformin had significant decreases on IGF-1 (mean difference in change: -5.50 ng/mL, P = 0.02) and IGF1:IGFBP3 molar ratio (mean difference in change: -0.0119, P = 0.011) at 3 months. The significant decrease of IGF-1 remained in participants with obesity at 6 months (mean difference in change: -7.2 ng/mL; 95% CI: -13.3 to -1.1), but not in participants with overweight (P for interaction = 0.045). There were no significant differences in changes between the coach-directed and self-directed groups. There were no differences in outcomes at 12 months. CONCLUSIONS: In cancer survivors with obesity, metformin may have a short-term effect on IGF-1 reduction that wanes over time.

Systematic evaluation of structure-property relationships and pharmacokinetics in 6-(hetero)aryl-substituted matched pair analogs of amiloride and 5-(N,N-hexamethylene)amiloride.

The K+-sparing diuretic amiloride elicits anticancer activities in multiple animal models. During our recent medicinal chemistry campaign aiming to identify amiloride analogs with improved properties for potential use in cancer, we discovered novel 6-(hetero)aryl-substituted amiloride and 5-(N,N-hexamethylene)amiloride (HMA) analogs with up to 100-fold higher potencies than the parent compounds against urokinase plasminogen activator (uPA), one of amiloride's putative anticancer targets, and no diuretic or antikaliuretic effects. Here, we report the systematic evaluation of structure-property relationships (lipophilicity, aqueous solubility and in vitro metabolic stability in human and mouse liver microsomes) in twelve matched pair analogs selected from our 6-substituted amiloride and HMA libraries. Mouse plasma stability, plasma protein binding, Caco-2 cell permeability, cardiac ion channel activity and pharmacokinetics in mice (PO and IV) and rats (IV) are described alongside amiloride and HMA comparators for a subset of the four most promising matched-pair analogs. The findings combined with earlier uPA activity/selectivity and other data ultimately drove selection of two analogs (AA1-39 and AA1-41) that showed efficacy in separate mouse cancer metastasis studies.

Efficacy of endotracheal tube suctioning in intubated intensive care unit patients determined by in vivo catheter-based optical coherence tomography-a pilot study.

BACKGROUND: Mechanical ventilation using an endotracheal tube (ETT) is one of the critical interventions given to patients in the intensive care unit (ICU). ETTs are associated with the formation of biofilms, placing patients at increased risk for developing ventilator-associated pneumonia (VAP). ETT suctioning is used to remove secretions, reduce bacterial colonization, and reduce the rate of biofilm formation. However, current standard-of-care suctioning procedures do not adequately eliminate all secretions from the ETT. METHODS: This observational study was conducted in a cohort of 4 subjects admitted to the ICU and intubated with an ETT, irrespective of ethnicity, gender, or race. A total of 23 suctioning procedures were evaluated with in vivo three-dimensional (3D) optical coherence tomography (OCT) imaging, before and after suctioning. A secretion density metric was derived from the OCT data to quantify the amount of secretions present within the ETT, and an attenuation coefficient metric was derived to detect and quantify the presence of biofilms. Analyzed OCT images were correlated with clinical and microscopy data. RESULTS: Data obtained suggests that the current standard-of-care suctioning procedure is inefficient at clearing secretions or preventing the formation of biofilms. The presence of biofilms was corroborated with both post-intubation microscopy of the ETTs, as well as with clinical data. CONCLUSIONS: We conclude that the standard-of-care suctioning method does not eliminate secretions nor reduce the formation of biofilm in ETTs. Our in situ imaging method was sensitive to the presence of secretions, biofilms, and quantitative, and can be used for investigating different suctioning protocols in the future.

Best Practices to Support Early-Stage Career URM Students with Virtual Enhancements to In-Person Experiential Learning.

STEM training of college-bound and college students has reliably employed hands-on experiential learning by placing students in on-campus research settings. Dana-Farber/Harvard Cancer Center's Young Empowered Scientists for ContinUed Research Engagement (DF/HCC's YES for CURE) program introduces Massachusetts high school and college students from underrepresented populations to cancer research by immersing them in scientific and nursing research environments. Amidst the COVID-19 pandemic, the 2020 summer program was re-designed and delivered virtually for 45 students. Because the program spans three years, we could evaluate the experiences of 18 students (cohort 2) who completed the 2019 (pre-pandemic) and 2020 (pandemic) summer programs. Analysis of cohort 2 data revealed three areas where students felt their competence improved with virtual programming (i.e., effective communication of ideas, access to high caliber speakers, engagement with program leaders) and two areas where it declined significantly (i.e., engaging other students, learning lab material). Additionally, student-reported competence to perform 21 scientific research and seven critical thinking processes were not negatively impacted by the virtual transition. Herein, we describe the adaptation of DF/HCC's YES for CURE program to a virtual format and the impact on students as a resource for institutions interested in enhancing their STEM training programs with virtual programming.

Translating research into practice: Protocol for a community-engaged, stepped wedge randomized trial to reduce disparities in breast cancer treatment through a regional patient navigation collaborative.

BACKGROUND: Racial and socioeconomic disparities in breast cancer mortality persist. In Boston, MA, Black, Non-Hispanic women and Medicaid-insured individuals are 2-3 times more likely to have delays in treatment compared to White or privately insured women. While evidence-based care coordination strategies for reducing delays exist, they are not systematically implemented across healthcare settings. METHODS: Translating Research Into Practice (TRIP) utilizes community engaged research methods to address breast cancer care delivery disparities. Four Massachusetts Clinical and Translational Science Institute (CTSI) hubs collaborated with the Boston Breast Cancer Equity Coalition (The Coalition) to implement an evidence-based care coordination intervention for Boston residents at risk for delays in breast cancer care. The Coalition used a community-driven process to define the problem of care delivery disparities, identify the target population, and develop a rigorous pragmatic approach. We chose a cluster-randomized, stepped-wedge hybrid type I effectiveness-implementation study design. The intervention implements three evidence-based strategies: patient navigation services, a shared patient registry for use across academic medical centers, and a web-based social determinants of health platform to identify and address barriers to care. Primary clinical outcomes include time to first treatment and receipt of guideline-concordant treatment, which are captured through electronic health records abstraction. We will use mixed methods to collect the secondary implementation outcomes of acceptability, adoption/penetration, fidelity, sustainability and cost. CONCLUSION: TRIP utilizes an innovative community-driven research strategy, focused on interdisciplinary collaborations, to design and implement a translational science study that aims to more efficiently integrate proven health services interventions into clinical practice.

Lead Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series for the Treatment of Malaria.

Malaria puts at risk nearly half the world's population and causes high mortality in sub-Saharan Africa, while drug resistance threatens current therapies. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) is a validated target for malaria treatment based on our finding that triazolopyrimidine DSM265 (1) showed efficacy in clinical studies. Herein, we describe optimization of a pyrrole-based series identified using a target-based DHODH screen. Compounds with nanomolar potency versus Plasmodium DHODH and Plasmodium parasites were identified with good pharmacological properties. X-ray studies showed that the pyrroles bind an alternative enzyme conformation from 1 leading to improved species selectivity versus mammalian enzymes and equivalent activity on Plasmodium falciparum and Plasmodium vivax DHODH. The best lead DSM502 (37) showed in vivo efficacy at similar levels of blood exposure to 1, although metabolic stability was reduced. Overall, the pyrrole-based DHODH inhibitors provide an attractive alternative scaffold for the development of new antimalarial compounds.

Structure-Activity Relationship of Antischistosomal Ozonide Carboxylic Acids.

Semisynthetic artemisinins and other bioactive peroxides are best known for their powerful antimalarial activities, and they also show substantial activity against schistosomes-another hemoglobin-degrading pathogen. Building on this discovery, we now describe the initial structure-activity relationship (SAR) of antischistosomal ozonide carboxylic acids OZ418 (2) and OZ165 (3). Irrespective of lipophilicity, these ozonide weak acids have relatively low aqueous solubilities and high protein binding values. Ozonides with para-substituted carboxymethoxy and N-benzylglycine substituents had high antischistosomal efficacies. It was possible to increase solubility, decrease protein binding, and maintain the high antischistosomal activity in mice infected with juvenile and adult Schistosoma mansoni by incorporating a weak base functional group in these compounds. In some cases, adding polar functional groups and heteroatoms to the spiroadamantane substructure increased the solubility and metabolic stability, but in all cases decreased the antischistosomal activity.

Discovery of Acylsulfonohydrazide-Derived Inhibitors of the Lysine Acetyltransferase, KAT6A, as Potent Senescence-Inducing Anti-Cancer Agents.

A high-throughput screen designed to discover new inhibitors of histone acetyltransferase KAT6A uncovered CTX-0124143 (1), a unique aryl acylsulfonohydrazide with an IC50 of 1.0 µM. Using this acylsulfonohydrazide as a template, we herein disclose the results of our extensive structure-activity relationship investigations, which resulted in the discovery of advanced compounds such as 55 and 80. These two compounds represent significant improvements on our recently reported prototypical lead WM-8014 (3) as they are not only equivalently potent as inhibitors of KAT6A but are less lipophilic and significantly more stable to microsomal degradation. Furthermore, during this process, we discovered a distinct structural subclass that contains key 2-fluorobenzenesulfonyl and phenylpyridine motifs, culminating in the discovery of WM-1119 (4). This compound is a highly potent KAT6A inhibitor (IC50 = 6.3 nM; KD = 0.002 µM), competes with Ac-CoA by binding to the Ac-CoA binding site, and has an oral bioavailability of 56% in rats.

Standardized activities for lay patient navigators in breast cancer care: Recommendations from a citywide implementation study.

BACKGROUND: There is a need for guidelines on patient navigation activities to promote both the quality of patient navigation and the standards of reimbursement for these services because a lack of reimbursement is a major barrier to the implementation, maintenance, and sustainability of these programs. METHODS: A broad community-based participatory research process was used to identify the needs of patients for navigation. A panel of stakeholders of clinical providers was convened to identify specific activities for navigators to address the needs of patients and providers with the explicit goal of reducing delays in the initiation of cancer treatment and improving adherence to the care plan. RESULTS: Specific activities were identified that could be generalized to all patient navigation programs for care during active cancer management to address the needs of vulnerable communities. CONCLUSIONS: Oncology programs that seek to implement lay patient navigation may benefit from the adoption of these activities for quality monitoring. Such activities are necessary as we consider reimbursement strategies for navigators without clinical training or licensure.

Falcipain Inhibitors Based on the Natural Product Gallinamide A Are Potent in Vitro and in Vivo Antimalarials.

A library of analogues of the cyanobacterium-derived depsipeptide natural product gallinamide A were designed and prepared using a highly efficient and convergent synthetic route. Analogues were shown to exhibit potent inhibitory activity against the Plasmodium falciparum cysteine proteases falcipain 2 and falcipain 3 and against cultured chloroquine-sensitive (3D7) and chloroquine-resistant (W2) strains of P. falciparum. Three lead compounds were selected for evaluation of in vivo efficacy against Plasmodium berghei infection in mice on the basis of their improved blood, plasma, and microsomal stability profiles compared with the parent natural product. One of the lead analogues cured P. berghei-infected mice in the Peters 4 day-suppressive test when administered 25 mg kg-1 intraperitoneally daily for 4 days. The compound was also capable of clearing parasites in established infections at 50 mg kg-1 intraperitoneally daily for 4 days and exhibited moderate activity when administered as four oral doses of 100 mg kg-1.

Using Human Plasma as an Assay Medium in Caco-2 Studies Improves Mass Balance for Lipophilic Compounds.

PURPOSE: To examine the utility of human plasma as an assay medium in Caco-2 permeability studies to overcome poor mass balance and inadequate sink conditions frequently encountered with lipophilic compounds. METHODS: Caco-2 permeability was assessed for reference compounds with known transport mechanisms using either pH 7.4 buffer or human plasma as the assay medium in both the apical and basolateral chambers. When using plasma, Papp values were corrected for the unbound fraction in the donor chamber. The utility of the approach was assessed by measuring the permeability of selected antimalarial compounds using the two assay media. RESULTS: Caco-2 cell monolayer integrity and P-gp transporter function were unaffected by the presence of human plasma in the donor and acceptor chambers. For many of the reference compounds having good mass balance with buffer as the medium, higher Papp values were observed with plasma, likely due to improved acceptor sink conditions. The lipophilic antimalarial compounds exhibited low mass balance with buffer, however the use of plasma markedly improved mass balance allowing the determination of more reliable Papp values. CONCLUSIONS: The results support the utility of human plasma as an alternate Caco-2 assay medium to improve mass balance and permeability measurements for lipophilic compounds.

Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth.

Acetylation of histones by lysine acetyltransferases (KATs) is essential for chromatin organization and function1. Among the genes coding for the MYST family of KATs (KAT5-KAT8) are the oncogenes KAT6A (also known as MOZ) and KAT6B (also known as MORF and QKF)2,3. KAT6A has essential roles in normal haematopoietic stem cells4-6 and is the target of recurrent chromosomal translocations, causing acute myeloid leukaemia7,8. Similarly, chromosomal translocations in KAT6B have been identified in diverse cancers8. KAT6A suppresses cellular senescence through the regulation of suppressors of the CDKN2A locus9,10, a function that requires its KAT activity10. Loss of one allele of KAT6A extends the median survival of mice with MYC-induced lymphoma from 105 to 413 days11. These findings suggest that inhibition of KAT6A and KAT6B may provide a therapeutic benefit in cancer. Here we present highly potent, selective inhibitors of KAT6A and KAT6B, denoted WM-8014 and WM-1119. Biochemical and structural studies demonstrate that these compounds are reversible competitors of acetyl coenzyme A and inhibit MYST-catalysed histone acetylation. WM-8014 and WM-1119 induce cell cycle exit and cellular senescence without causing DNA damage. Senescence is INK4A/ARF-dependent and is accompanied by changes in gene expression that are typical of loss of KAT6A function. WM-8014 potentiates oncogene-induced senescence in vitro and in a zebrafish model of hepatocellular carcinoma. WM-1119, which has increased bioavailability, arrests the progression of lymphoma in mice. We anticipate that this class of inhibitors will help to accelerate the development of therapeutics that target gene transcription regulated by histone acetylation.