PMID- 37634595 OWN - NLM STAT- MEDLINE DCOM- 20231011 LR - 20231011 IS - 1873-2968 (Electronic) IS - 0006-2952 (Linking) VI - 216 DP - 2023 Oct TI - Triazolothiadiazine derivative positively modulates CXCR4 signaling and improves diabetic wound healing. PG - 115764 LID - S0006-2952(23)00355-6 [pii] LID - 10.1016/j.bcp.2023.115764 [doi] AB - Development of specific therapies that target and accelerate diabetic wound repair is an urgent need to alleviate pain and suffering and the huge socioeconomic burden of this debilitating disease. C-X-C Motif Chemokine Ligand 12 (CXCL12) also know an stromal cell-derived factor 1alpha (SDF-1alpha) is a chemokine that binds the CXC chemokine receptor type 4 (CXCR4) and activates downstream signaling resulting in recruitment of hematopoietic cells to locations of tissue injury and promotes tissue repair. In diabetes, low expression of CXCL12 correlates with impaired wound healing. Activation of CXCR4 receptor signaling with agonists or positive allosteric modulators (PAMs) provides a potential for small molecule therapeutic discovery and development. We recently reported high throughput screening and identification of the CXCR4 partial agonist UCUF-728, characterization of in vitro activity and reduced wound closure time in diabetic mice at 100 muM as a proof-of-concept study. We report here, the discovery of a second chemical scaffold demonstrating increased agonist potency and represented by thiadiazine derivative, UCUF-965. UCUF-965 is a potent partial agonist of beta-arrestin recruitment in CXCR4 receptor overexpressing cell line. Furthermore, UCUF-965 potentiates the CXCL12 maximal response in cAMP signaling pathway, activates CXCL12 stimulated migration in lymphoblast cells and modulates the levels of specific microRNA involved in the complex wound repair process, specifically in mouse fibroblasts. Our results indicate that UCUF-965 acts as a PAM agonist of the CXCR4 receptor. Furthermore, UCUF-965 enhanced angiogenesis markers and reduced wound healing time by 36% at 10.0 muM in diabetic mice models compared to untreated control. CI - Copyright (c) 2023. Published by Elsevier Inc. FAU - Peddibhotla, Satyamaheshwar AU - Peddibhotla S AD - Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA. FAU - Caples, Karly AU - Caples K AD - Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA. FAU - Mehta, Alka AU - Mehta A AD - Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA. FAU - Chen, Qi-Yin AU - Chen QY AD - Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA. FAU - Hu, Junyi AU - Hu J AD - Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA. FAU - Idlett-Ali, Shaquia AU - Idlett-Ali S AD - Laboratory for Fetal and Regenerative Biology, Department of Surgery, University of Colorado Denver - Anschutz Medical Campus and Children's Hospital Colorado, Aurora, CO 80045, USA. FAU - Zhang, Liping AU - Zhang L AD - Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA. FAU - Zgheib, Carlos AU - Zgheib C AD - Laboratory for Fetal and Regenerative Biology, Department of Surgery, University of Colorado Denver - Anschutz Medical Campus and Children's Hospital Colorado, Aurora, CO 80045, USA. FAU - Xu, Junwang AU - Xu J AD - Laboratory for Fetal and Regenerative Biology, Department of Surgery, University of Colorado Denver - Anschutz Medical Campus and Children's Hospital Colorado, Aurora, CO 80045, USA; Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA. FAU - Liechty, Kenneth W AU - Liechty KW AD - Laboratory for Fetal and Regenerative Biology, Department of Surgery, University of Colorado Denver - Anschutz Medical Campus and Children's Hospital Colorado, Aurora, CO 80045, USA. Electronic address: kliechty@arizona.edu. FAU - Malany, Siobhan AU - Malany S AD - Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA. Electronic address: smalany@cop.ufl.edu. LA - eng GR - R01 DK126371/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20230825 PL - England TA - Biochem Pharmacol JT - Biochemical pharmacology JID - 0101032 RN - 0 (Chemokine CXCL12) RN - 0 (Receptors, CXCR4) SB - IM MH - Animals MH - Mice MH - Cell Movement/physiology MH - Chemokine CXCL12/metabolism MH - *Diabetes Mellitus, Experimental/drug therapy/genetics/immunology MH - Hematopoietic Stem Cells MH - *Receptors, CXCR4/agonists/genetics/metabolism MH - Signal Transduction MH - *Wound Healing/drug effects/genetics/physiology OTO - NOTNLM OT - CXCR4 receptor agonists OT - Diabetic wound healing OT - High-throughput screening OT - Lymphoblast signaling OT - Positive allosteric modulator agonist OT - Triazolothiadizine OT - UCUF965 COIS- Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2023/08/28 00:41 MHDA- 2023/10/02 06:42 CRDT- 2023/08/27 19:23 PHST- 2023/07/02 00:00 [received] PHST- 2023/08/17 00:00 [revised] PHST- 2023/08/21 00:00 [accepted] PHST- 2023/10/02 06:42 [medline] PHST- 2023/08/28 00:41 [pubmed] PHST- 2023/08/27 19:23 [entrez] AID - S0006-2952(23)00355-6 [pii] AID - 10.1016/j.bcp.2023.115764 [doi] PST - ppublish SO - Biochem Pharmacol. 2023 Oct;216:115764. doi: 10.1016/j.bcp.2023.115764. Epub 2023 Aug 25.