Author: Verhee, Annick ; Eyckerman, Sven ; Van Vlierberghe, Pieter ; Staessens, Eleni ; Goossens, Steven ; De Bosscher, Karolien ; Declerck, Fien ; Offner, Fritz ; Clarisse, Dorien ; Van Trimpont, Maaike ; Luyckx, Bert ; T'Sas, Sara

Glucocorticoids (GC) are cornerstone drugs in the treatment of multiple myeloma (MM). Because MM cells exploit the bone marrow microenvironment to obtain growth and survival signals, resistance to glucocorticoid-induced apoptosis emerges, yet the underlying mechanisms remain poorly characterized. Here, we identify that the chemokine receptor CCR1, together with its main ligand CCL3, plays a pivotal role in reducing the glucocorticoid sensitivity of MM cells. We show that blocking CCR1 signaling with the antagonist BX471 enhances the anti-MM effects of the glucocorticoid dexamethasone in MM cell lines, primary patient material and a myeloma xenograft mouse model. Mechanistically, the drug combination shifts the balance between pro- and antiapoptotic proteins towards apoptosis and deregulates lysosomal proteins. Our findings suggest that CCR1 may play a role in glucocorticoid resistance, as the GC-induced downregulation of CCR1 mRNA and protein is blunted in a GC-resistance onset model. Moreover, we demonstrate that inhibiting CCR1 partially reverses this resistance, providing a promising strategy for resensitizing MM cells to GC treatment.

01 Feb 2025·International Immunopharmacology

Blocking the CCL5/CCL7-CCR1 axis regulates macrophage polarization through NF-κB pathway to alleviate the progression of osteoarthritis

Article

Author: You, Hong-Bo ; Xu, Hanqing ; Huang, Xiao-Jian ; He, Yi ; Meng, Chen ; Liu, Qingyi ; Chen, Sheng

OBJECTIVETo study the effect of CCR1 and its ligands on macrophage polarization and evaluate its effect on chondrocytes in relieving the progression of osteoarthritis.METHODSRAW cells were polarized to M1/M2 subtype, and then different concentrations of BX471 were added to selectively inhibit CCR1. The polarization of the cells was detected by RT-qPCR, immunofluorescence and flow cytometry. CCL5 and CCL7 genes were silenced by SiRNA and its role in macrophage polarization was analyzed. Macrophage conditioned medium was further used to stimulate chondrocytes. Histological observation was carried out on models of medial meniscus (DMM) with or without BX471 treatment.RESULTSWe found that blocking of CCR1 and silencing of its ligand, CCL5 and CCL7, reduced the polarization of M1 macrophages. In terms of mechanism, we found that blocking CCR1 could reduce the activation of NF-κB pathway and inhibit the phosphorylation of IKK, IκBα and P65. In addition, blocking of CCR1 could also reduce cartilage injury induced by macrophage conditioned medium. In vivo, blocking of CCR1 reduced the infiltration and accumulation of M1 macrophages and alleviated articular cartilage injury.CONCLUSIONCCL5/CCL7-CCR1 axis was involved in macrophage polarization, and blocking it could reduce synovitis and alleviate the process of OA.

01 Feb 2025·Neuropharmacology

CCR1 antagonist as a potential modulator of inflammatory, autophagic, and apoptotic markers in spinal cord injury

Article

Author: Campolo, Michela ; Hasan, Ahmed ; Ardizzone, Alessio ; Repici, Alberto ; Catalfamo, Antonio ; Esposito, Emanuela ; Bova, Valentina ; Mannino, Deborah ; Paterniti, Irene ; Capra, Anna Paola

Spinal cord injury (SCI) leads to severe and lasting impairments in motor and sensory functions. The intense inflammatory response following SCI is a significant challenge, and autophagy has emerged as a key factor in the recovery process. The C-C chemokine receptor type 1 (CCR1), a G-protein coupled receptor, plays a crucial role in managing the chemokine response under stress. BX471, a selective and potent CCR1 antagonist, has been explored in various disease contexts for its therapeutic potential. In this study, we assessed the effects of BX471 in a mouse model of SCI. The treatment was administered at doses of 3 and 10 mg/kg, 1 h and 6 h after the injury occurred. Results showed that BX471 significantly improved tissue structure by positively influencing autophagy and reducing inflammation. Inflammatory markers, including CCR1 ligands RANTES, MIP-1α, TNF-α, and IL-1β, were measured using Western blot analysis. Additionally, histological evaluations revealed that BX471 effectively decreased infiltration and reduced astrocyte and microglial activation, supporting the idea that enhancing autophagy through CCR1 inhibition could promote neuronal survival. The highest efficacy was observed at the 10 mg/kg dose, leading to optimal out-comes across the assessments. These findings suggest that CCR1 blockade with BX471 may offer a promising therapeutic strategy for SCI, addressing a critical gap in the current pharmacological treatment options.

100 Deals associated with BX-471

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Indication	Highest Phase	Country/Location	Organization	Date
Alzheimer Disease	Phase 2	Germany	-	-
Alzheimer Disease	Phase 2	-	Bayer AG	-
Endometriosis	Phase 2	Europe	Bayer HealthCare Pharmaceuticals, Inc.	-
Endometriosis	Phase 2	Europe	Bayer HealthCare Pharmaceuticals, Inc.	-
Multiple Myeloma	Phase 2	-	Bayer AG	-
Multiple Sclerosis	Phase 2	Europe	-	-
Multiple Sclerosis	Phase 2	-	Bayer AG	-
Psoriasis	Phase 2	-	Bayer AG	-
Psoriasis	Phase 2	Europe	-	-

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