Abstract 4: Discovery of novel and highly potent small molecule inhibitors of chemokine receptor CXCR4

Xiong, Fei; Meng, Qingwei; Xiao, Fang; Zhu, Siyu; Huang, Yazi; J, An; Xu, Yan; Huang, Ziwei

doi:10.1158/1538-7445.sabcs18-4

Cited by 2 publications

(3 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…On the basis of our representative compound HF50731 (29), we have developed a new highly potent small molecule analog named HF51116, which features an unsymmetrical polyamine ( Figure 1A). HF51116 binds strongly to CXCR4 with the IC50 of 12 nM in competitive binding with 12G5 (26). We examined the compositions and dynamics of different PB cells in mice following subcutaneous injection of HF51116.…”

Section: Mobilization Of Different Peripheral Blood Cells In Micementioning

confidence: 99%

“…In the present study, we describe the in vivo HSC mobilization e cacy and mode of action of HF51116 (25), a novel CXCR4 antagonist developed by our group. HF51116 possesses very high CXCR4 binding a nity (IC 50 = 12 nM) (26) and potently mobilizes HSCs from the bone marrow (BM) to the peripheral blood (PB). We have fully evaluated the e cacy of HF51116 both in mice and monkeys.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A Novel Small Molecule CXCR4 Antagonist Potently Mobilizes Hematopoietic Stem Cells in Mice and Monkeys

Fang

Mao

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Background Hematopoietic stem cell (HSC) transplantation is an effective treatment strategy for many types of diseases. Peripheral blood (PB) is the most commonly used source of bone marrow (BM)-derived stem cells for current HSC transplantation. However, PB usually contains very few HSCs under normal conditions, as these cells are normally retained within the BM. This retention depends on the interaction between the CXC chemokine receptor 4 (CXCR4) expressed on the HSCs and its natural chemokine ligand, stromal cell-derived factor (SDF)-1α (also named CXCL12) present in the BM stromal microenvironment. In clinical practice, blocking this interaction with a CXCR4 antagonist can induce the rapid mobilization of HSCs from the BM into the PB.Methods C3H/HEJ, DBA/2, CD45.1+, CD45.2+ mice and monkeys were employed in colony-forming unit (CFU) assays, flow cytometry assays, and competitive/non-competitive transplantation assays, to assess the short-term mobilization efficacy of HF51116 and the long-term repopulating (LTR) ability of HSCs. Kinetics of different blood cells and the concentration of HF51116 in PB were also explored by blood routine examinations and pharmacokinetic assays. Results In this paper, we report that a novel small molecule CXCR4 antagonist, HF51116, which was designed and synthesized by our laboratory, can rapidly and potently mobilize HSCs from BM to PB in mice and monkeys. HF51116 not only mobilized HSCs when used alone but also synergized with the mobilizing effects of granulocyte-colony stimulating factor (G-CSF) after co-administration. Following mobilization by HF51116 and G-CSF, the long-term repopulating (LTR) and self-renewing HSCs were sufficiently engrafted in primary and secondary lethally irradiated mice and were able to rescue and support long-term mouse survival. In monkeys, HF51116 exhibited strong HSC mobilization activity and quickly reached the highest in vivo blood drug concentration. Conclusions These results demonstrate that HF51116 is a new promising stem cell mobilizer which specifically targets CXCR4 and merits further preclinical and clinical studies.

show abstract

Section: Mobilization Of Different Peripheral Blood Cells In Micementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Novel Small Molecule CXCR4 Antagonist Potently Mobilizes Hematopoietic Stem Cells in Mice and Monkeys

Fang

Mao

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…In the present study, we report the in vivo HSC mobilization e cacy of HF51116 (25), a novel CXCR4 antagonist developed recently by our laboratories. HF51116 possesses very high CXCR4 binding a nity (IC 50 = 12 nM) (26) and potently mobilizes HSCs from the bone marrow (BM) to the peripheral blood (PB).…”

Section: Introductionmentioning

confidence: 99%

A novel small molecule CXCR4 antagonist potently mobilizes hematopoietic stem cells in mice and monkeys

Fang

Mao

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

Abstract 4: Discovery of novel and highly potent small molecule inhibitors of chemokine receptor CXCR4

Cited by 2 publications

References 0 publications

A Novel Small Molecule CXCR4 Antagonist Potently Mobilizes Hematopoietic Stem Cells in Mice and Monkeys

A Novel Small Molecule CXCR4 Antagonist Potently Mobilizes Hematopoietic Stem Cells in Mice and Monkeys

A novel small molecule CXCR4 antagonist potently mobilizes hematopoietic stem cells in mice and monkeys

Contact Info

Product

Resources

About