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

轉載：

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.

之後，根據化合物(wù)2的骨架，合成并研究了一系列的T140衍生物(wù)，用(yòng)D-Glu和/或L-Cit取代堿性氨基酸殘基，目的是進一步降低化合物(wù)2的非特異性結合與細胞毒性。其中(zhōng)化合物(wù)3（TN14003）具(jù)有(yǒu)較強的抗HIV活性和較低的細胞毒性。研究發現，化合物(wù)3在小(xiǎo)鼠血清中(zhōng)穩定，但在大鼠肝髒中(zhōng)不穩定，這是由于親本肽中(zhōng)N端Arg1-Arg2-L-3-(2-naphthyl)alanine(Nal)3殘基的缺失。于是，進一步将化合物(wù)3N端乙酰化，設計合成并獲得了一種新(xīn)的先導化合物(wù)4（Ac-TN14003），該化合物(wù)具(jù)有(yǒu)高選擇性指數，并在血清和肝髒勻漿中(zhōng)具(jù)有(yǒu)更高的穩定性，詳細數據參見下圖。

為(wèi)了進一步開發具(jù)有(yǒu)更高生物(wù)穩定性的有(yǒu)效化合物(wù)，與化合物(wù)4類似，一系列N端修飾的TN14003被合成出來，其中(zhōng)化合物(wù)5（TF14016）顯示出強的抗HIV活性，表明T140類似物(wù)N端的4-氟苯甲酰片段構成了一種新(xīn)的基于T140的CXCR4拮抗劑藥效團。

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

If there is any infringement, please contact us and we will delete it.