Sp457ccr2 Inhibitor Ccx140 Effective in Phase 2 Clinical Trial in Diabetic Nephropathy

Zeeuw, Dick de; Henkel, Elena; Psottová, Jana; Paragh, György; Mehling, Heidrun; Hasslacher, C.; Potarca, Antonia; Bekker, Pirow; Schall, Thomas J.

doi:10.1093/ndt/gfv195.01

Cited by 4 publications

(5 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…13 Although CMML monocytes do not overexpress the CCL2 gene, the cytokine can be increased in the plasma of patients with CMML 40 and may further promote the resistance of CMML monocytes to apoptosis. Antagonizing CCR2 with inhibitors that are currently tested in the treatment of diabetes mellitus, 41 cancer, 42 and HIV1 infection 43 could be an alternative to MEK inhibitors to promote the efficacy of MCL1 inhibition in CMML.…”

Section: Discussionmentioning

confidence: 99%

Cytokine-like protein 1–induced survival of monocytes suggests a combined strategy targeting MCL1 and MAPK in CMML

Sevin

Debeurme

Laplane

et al. 2021

Blood

View full text Add to dashboard Cite

Mouse models of chronic myeloid malignancies suggest that targeting mature cells of the malignant clone disrupts feedback loops that promote disease expansion. Here, we show that, in chronic myelomonocytic leukemia (CMML), monocytes that accumulate in the peripheral blood show a decreased propensity to die by apoptosis. BH3 profiling demonstrates their addiction to MCL1 (myeloid cell leukemia-1), which can be targeted with the small molecule inhibitor S63845. RNA sequencing and DNA methylation pattern analysis both point also to the implication of the MAPK (mitogen-activated protein kinase) pathway in the resistance of CMML monocytes to death and reveal an autocrine pathway in which the secreted cytokine CYTL1 (Cytokine-like protein 1) promotes ERK (extracellular signal-regulated kinase) activation through CCR2 (C-C chemokine receptor type 2). Combined MAPK and MCL1 inhibition restores apoptosis of CMML patient monocytes and reduces the expansion of patient-derived xenografts in mice. These results designate the combined inhibition of MCL1 and MAPK as a promising approach to slow down CMML progression by inducing leukemic monocyte apoptosis.

show abstract

Section: Discussionmentioning

confidence: 99%

Cytokine-like protein 1–induced survival of monocytes suggests a combined strategy targeting MCL1 and MAPK in CMML

Sevin

Debeurme

Laplane

et al. 2021

Blood

View full text Add to dashboard Cite

show abstract

“…These patients were already treated with RAS blockers. Significant improvement in the slope of decline of GFR over that achieved with the standard of care treatment was also observed beside the improved glycemic control [6] . The results of phase 3, however, did not confirm the signi ficant impact on GFR but did confirm the antiproteinuric and the glycemic favorable outcomes reported in phase 2 [154] .…”

Section: Sharaf El Din Uaa Et Al Stop Chronic Kidney Disease Progrementioning

confidence: 81%

“…Klotho is an anti-senescence protein [6] . It exists in 2 forms: The transmembrane and the soluble secreted form [163] .…”

Section: Sharaf El Din Uaa Et Al Stop Chronic Kidney Disease Progrementioning

confidence: 99%

“…Klotho is detected as a soluble protein in body fluids including blood, CSF and urine [164] . The highest expression of Klotho is in the kidney and the brain [6] , but it is also expressed in parathyroid gland [165] and heart [166] with less abundance. Klotho protein is a β-glucuronidase.…”

Section: Sharaf El Din Uaa Et Al Stop Chronic Kidney Disease Progrementioning

confidence: 99%

“…The recent discoveries of novel mechanisms underlying CKD progression opened the gate for more comprehensive understanding of the pathophysiology of CKD progression and the development of new therapeutic strategies. The role of chemokines in the recruitment of inflammatory cells into the kidney of a variety underlying diseases has opened the gate for new promising therapeutic modalities [5,6] . The intensive studies done on Klotho and fibroblast growth factor 23 (FGF23) and their role in the control of renal phosphate handling [7] , and their unique anti-aging properties [8,9] have disclosed appreciable data concerning their action on vascular calcification (V.C.)…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Stop chronic kidney disease progression: Time is approaching

Din¹,

Salem²,

Abdulazim³

2016

WJN

View full text Add to dashboard Cite

Progression of chronic kidney disease (CKD) is inevitable. However, the last decade has witnessed tremendous achievements in this field. Today we are optimistic; the dream of withholding this progression is about to be realistic. The recent discoveries in the field of CKD management involved most of the individual diseases leading the patients to end-stage renal disease. Most of these advances involved patients suffering diabetic kidney disease, chronic glomerulonephritis, polycystic kidney disease, renal amyloidosis and chronic tubulointerstitial disease. The chronic systemic inflammatory status and increased oxidative stress were also investigated. This inflammatory status influences the antisenescence Klotho gene expression. The role of Klotho in CKD progression together with its therapeutic value are explored. The role of gut as a major source of inflammation, the pathogenesis of intestinal mucosal barrier damage, the role of intestinal alkaline phosphatase and the dietary and therapeutic implications add a novel therapeutic tool to delay CKD progression.

show abstract

Developing Treatments for Chronic Kidney Disease in the 21st Century

Breyer

Suszták

2016

Seminars in Nephrology

View full text Add to dashboard Cite

Summary Chronic kidney disease (CKD) is a lethal and rapidly increasing burden on society. Despite this, there are relatively few therapies in development for the treatment of CKD. Several recent costly phase 3 trials have failed to provide improved renal outcomes, diminishing interest in pharmaceutical investment. Furthermore, poor patient, physician, and payer awareness of CKD as a diagnosis has contributed to slow trial enrollment and successful implementation of these trials. Nevertheless, several therapeutics remain in development for the treatment of CKD, including mineralocorticoid-receptor antagonists, sodium/glucose cotransporter 2 inhibitors, anti-inflammatory drugs, and drugs that mitigate oxidative injury. Success of future CKD therapeutic trials will depend not only on improved understanding of disease pathogenesis, but also on improved trial enrollment rates, through increasing awareness of this disease by the public, policy makers, and the greater medical community.

show abstract

Sp457ccr2 Inhibitor Ccx140 Effective in Phase 2 Clinical Trial in Diabetic Nephropathy

Cited by 4 publications

References 0 publications

Cytokine-like protein 1–induced survival of monocytes suggests a combined strategy targeting MCL1 and MAPK in CMML

Cytokine-like protein 1–induced survival of monocytes suggests a combined strategy targeting MCL1 and MAPK in CMML

Stop chronic kidney disease progression: Time is approaching

Developing Treatments for Chronic Kidney Disease in the 21st Century

Contact Info

Product

Resources

About