Discovery of Motixafortide, a CXCR4 inhibitor, approved by the FDA for marketing, as analyzed by the Drug Crossing Cyber analysis

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Motixafortide (Aphexda) is a subcutaneous CXCR4 inhibitor approved by the FDA on August 8, 2023, for mobilizing stem cells in the collection and subsequent autologous transplantation treatment of multiple myeloma patients. Discovered by Kyoto University, Biolinerx is marketed and often used in combination with granulocyte colony-stimulating factor G-CSF: fligratim to mobilize patients' autologous hematopoietic stem cells for transplantation.

Initially, Motixafortide was developed as a therapeutic drug against HIV infection, while CXCR4, as a co receptor for the entry of the T-tropical HIV-1 strain, received widespread attention from researchers.

Compound 1 (T22) was first discovered to inhibit HIV-1 infection in T-cell lines by specifically binding to the chemokine receptor CXCR4, which is an 18 residue peptide amide with strong anti HIV activity. On this basis, researchers continued to search for and discover stronger and smaller CXCR4 inhibitor 2 (T140, anti HIV activity: 50%, effective concentration EC50=3.5nM, antagonistic effect of X4-HIV-1 entry: EC50=0.43nM, CC50=45 μ M). Detailed data are shown in the following figure.

之后，根据化合物2的骨架，合成并研究了一系列的T140衍生物，用D-Glu和/或L-Cit取代碱性氨基酸残基，目的是进一步降低化合物2的非特异性结合与细胞毒性。其中化合物3（TN14003）具有较强的抗HIV活性和较低的细胞毒性。研究发现，化合物3在小鼠血清中稳定，但在大鼠肝脏中不稳定，这是由于亲本肽中N端Arg1-Arg2-L-3-(2-naphthyl)alanine(Nal)3残基的缺失。于是，进一步将化合物3N端乙酰化，设计合成并获得了一种新的先导化合物4（Ac-TN14003），该化合物具有高选择性指数，并在血清和肝脏匀浆中具有更高的稳定性，详细数据参见下图。

为了进一步开发具有更高生物稳定性的有效化合物，与化合物4类似，一系列N端修饰的TN14003被合成出来，其中化合物5（TF14016）显示出强的抗HIV活性，表明T140类似物N端的4-氟苯甲酰片段构成了一种新的基于T140的CXCR4拮抗剂药效团。

In summary, the enhancement of the T140 pharmacophore has led to the development of a novel CXCR4 antagonist compound 6 (motxafortide), which exhibits very high anti HIV activity and higher biological stability.

Reprinting link: https://zhuanlan.zhihu.com/p/699543710

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