{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T13:23:19Z","timestamp":1787404999351,"version":"build-2736575974"},"reference-count":62,"publisher":"American Chemical Society (ACS)","issue":"8","license":[{"start":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T00:00:00Z","timestamp":1784937600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T00:00:00Z","timestamp":1784937600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T00:00:00Z","timestamp":1784937600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Small molecule targeting of suppressive myeloid immune checkpoints remains a major challenge in cancer immunotherapy, particularly for nonenzymatic receptors lacking conventional druggable active sites. Leukocyte immunoglobulin-like receptor B4 (LILRB4\/ILT3) is an immunosuppressive myeloid checkpoint implicated in tumor immune evasion, T-cell dysfunction, and resistance to immunotherapy across both solid and hematologic malignancies. Here, we report the discovery and characterization of GL-4512, a direct small molecule modulator of LILRB4 identified through a Dianthus-based temperature-related intensity change (TRIC) screening platform. Orthogonal biophysical studies, including microscale thermophoresis, surface plasmon resonance, and cellular thermal shift assays, confirmed direct target engagement with nanomolar affinity. Extensive microsecond molecular dynamics simulations combined with site-directed mutagenesis identified a previously unrecognized ligandable pocket within the flexible extracellular domain of LILRB4. Functionally, GL-4512 disrupted the immunosuppressive LILRB4-SCG2 signaling axis and suppressed downstream SHP1\/SHP2 and STAT3 signaling. In patient-derived colorectal cancer and acute myeloid leukemia coculture systems, pharmacological inhibition of LILRB4 restored antitumor immune activity, enhanced IFN-\u03b3 and IL-2 production, increased cytotoxic T-cell activation, and reduced tumor cell viability. GL-4512 additionally demonstrated favorable pharmacokinetic and safety properties supporting oral in vivo administration. In immunocompetent CT26 syngeneic colorectal tumors, once-daily oral treatment significantly suppressed tumor growth and enhanced intratumoral immune activation. Collectively, these findings establish LILRB4 as a tractable target for direct small molecule immunomodulation and support therapeutic targeting of suppressive myeloid immune checkpoints for cancer using nonbiologic modalities.<\/jats:p>","DOI":"10.1021\/acschembio.6c00486","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T05:08:52Z","timestamp":1785128932000},"page":"2040-2052","source":"Crossref","is-referenced-by-count":0,"title":["Direct Small Molecule Modulation of LILRB4 (ILT3)\nRestores Antitumor Immunity In Vivo and in Patient-Derived Cells"],"prefix":"10.1021","volume":"21","author":[{"given":"Somaya A.","family":"Abdel-Rahman","sequence":"first","affiliation":[{"name":"Weill Cornell Medicine , , , ,","place":["New York, New York, United States, 10065"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zamara","family":"Mariam","sequence":"additional","affiliation":[{"name":"Coventry University , , ,","place":["Coventry, U.K., CV1 5FB"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8780-2986","authenticated-orcid":true,"given":"Giuseppe","family":"Deganutti","sequence":"additional","affiliation":[{"name":"Coventry University , , ,","place":["Coventry, U.K., CV1 5FB"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9074-3331","authenticated-orcid":true,"given":"Moustafa T.","family":"Gabr","sequence":"additional","affiliation":[{"name":"Weill Cornell Medicine , , , ,","place":["New York, New York, United States, 10065"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,25]]},"reference":[{"key":"2026082208552798800_cit1","doi-asserted-by":"publisher","first-page":"1350","DOI":"10.1126\/science.aar4060","article-title":"Cancer immunotherapy\nusing checkpoint blockade","volume":"359","author":"Ribas","year":"2018","journal-title":"Science"},{"key":"2026082208552798800_cit2","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1016\/j.cell.2017.01.017","article-title":"Primary, adaptive,\nand acquired resistance to cancer immunotherapy","volume":"168","author":"Sharma","year":"2017","journal-title":"Cell"},{"key":"2026082208552798800_cit3","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.immuni.2019.12.011","article-title":"Top 10 challenges in cancer immunotherapy","volume":"52","author":"Hegde","year":"2020","journal-title":"Immunity"},{"key":"2026082208552798800_cit4","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1146\/annurev-pathol-042020-042741","article-title":"Immune checkpoint\ninhibitors for\nthe treatment of cancer: clinical impact and mechanisms of response\nand resistance","volume":"16","author":"Bagchi","year":"2021","journal-title":"Annu. 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