{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T02:05:34Z","timestamp":1777082734165,"version":"3.51.4"},"reference-count":33,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2024,12,7]],"date-time":"2024-12-07T00:00:00Z","timestamp":1733529600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH NCI","award":["R01-CA251361"],"award-info":[{"award-number":["R01-CA251361"]}]},{"name":"NIH NCI","award":["P30-CA046934"],"award-info":[{"award-number":["P30-CA046934"]}]},{"name":"Joseph Henry Edmondson Foundation, Colorado Springs, CO.","award":["R01-CA251361"],"award-info":[{"award-number":["R01-CA251361"]}]},{"name":"Joseph Henry Edmondson Foundation, Colorado Springs, CO.","award":["P30-CA046934"],"award-info":[{"award-number":["P30-CA046934"]}]},{"name":"Spanish Government through the Margarita Salas","award":["R01-CA251361"],"award-info":[{"award-number":["R01-CA251361"]}]},{"name":"Spanish Government through the Margarita Salas","award":["P30-CA046934"],"award-info":[{"award-number":["P30-CA046934"]}]},{"name":"University of Colorado Cancer Center","award":["R01-CA251361"],"award-info":[{"award-number":["R01-CA251361"]}]},{"name":"University of Colorado Cancer Center","award":["P30-CA046934"],"award-info":[{"award-number":["P30-CA046934"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Colorectal cancer (CRC) is one of the most prevalent and deadly forms of cancer. It is universally treated with a combination of the DNA damaging chemotherapy drugs irinotecan, 5-Fluorouracil (5-FU), and oxaliplatin. CHD1L is a novel oncogene that plays critical roles in chromatin remodeling and DNA damage repair, as well as the regulation of malignant gene expression. We show that an inhibitor of CHD1L, OTI-611, when combined with chemotherapy significantly increases DNA damage in CRC cell lines. OTI-611 also synergizes with SN-38, 5-FU, and oxaliplatin in killing CRC tumor organoids. We also demonstrate that, as in breast cancer, OTI-611 traps CHD1L, PARP1, and PARP2 onto chromatin. The entrapment of CHD1L causes the deprotection of PAR chains in the nucleus, ultimately resulting in cell death by CHD1Li-mediated PARthanatos, as measured by AIF translocation to the nucleus. Finally, the combination of low doses of OTI-611 with irinotecan significantly reduces tumor volume and extends survival in CRC xenograft mouse models compared to irinotecan alone. The combination of standard of care chemotherapy drugs with CHD1Li represents a promising advancement in future therapeutic strategies for CRC and other cancers driven by CHD1L.<\/jats:p>","DOI":"10.3390\/ijms252313160","type":"journal-article","created":{"date-parts":[[2024,12,9]],"date-time":"2024-12-09T04:01:37Z","timestamp":1733716897000},"page":"13160","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["CHD1L Inhibitor OTI-611 Synergizes with Chemotherapy to Enhance Antitumor Efficacy and Prolong Survival in Colorectal Cancer Mouse Models"],"prefix":"10.3390","volume":"25","author":[{"given":"Rita","family":"Sala","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, The Skaggs School of Pharmacy and Pharmaceutical Sciences, The University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1911-1523","authenticated-orcid":false,"given":"Hector","family":"Esquer","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, The Skaggs School of Pharmacy and Pharmaceutical Sciences, The University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"},{"name":"The CU Anschutz Center for Drug Discovery, Aurora, CO 80045, USA"},{"name":"The University of Colorado Cancer Center, Aurora, CO 80045, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timothy","family":"Kellett","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, The Skaggs School of Pharmacy and Pharmaceutical Sciences, The University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2734-972X","authenticated-orcid":false,"given":"Sophia","family":"Clune","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, The Skaggs School of Pharmacy and Pharmaceutical Sciences, The University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3995-121X","authenticated-orcid":false,"given":"Paul","family":"Awolade","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, The Skaggs School of Pharmacy and Pharmaceutical Sciences, The University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"},{"name":"The CU Anschutz Center for Drug Discovery, Aurora, CO 80045, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5841-2257","authenticated-orcid":false,"given":"Laura A.","family":"Pike","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, The Skaggs School of Pharmacy and Pharmaceutical Sciences, The University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, The Skaggs School of Pharmacy and Pharmaceutical Sciences, The University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"},{"name":"The CU Anschutz Center for Drug Discovery, Aurora, CO 80045, USA"},{"name":"The University of Colorado Cancer Center, Aurora, CO 80045, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wells A.","family":"Messersmith","sequence":"additional","affiliation":[{"name":"The CU Anschutz Center for Drug Discovery, Aurora, CO 80045, USA"},{"name":"The University of Colorado Cancer Center, Aurora, CO 80045, USA"},{"name":"Division of Medical Oncology, The School of Medicine, The University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9460-3862","authenticated-orcid":false,"given":"Daniel V.","family":"LaBarbera","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, The Skaggs School of Pharmacy and Pharmaceutical Sciences, The University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"},{"name":"The CU Anschutz Center for Drug Discovery, Aurora, CO 80045, USA"},{"name":"The University of Colorado Cancer Center, Aurora, CO 80045, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"229","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. 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