Author: Xu, Mengyang ; Xie, Xin ; Ma, Ting ; He, Linhong ; Qin, Tingsheng ; Zeng, Xianxia ; Zhang, Jie ; Wang, Nan ; Huang, Huaizheng ; Shi, Yamin ; Yang, Jie ; Ling, Zhen

BMX, a member of the Tec family of kinases, plays a pivotal role in the occurrence and progression of cancers and multiple chronic inflammations. However, there are rarely BMX inhibitors reported, and the signaling pathways mediated by BMX are still poorly understood. In this study, a series of novel BMX inhibitors bearing the core of 1,3,5-triazin-2-amine were designed and synthesized by structural modifications from the lead compound B1c. Among them, compound B6a irreversibly and selectively inhibited BMX (IC₅₀ = 12 nM) and displayed good antiproliferative activities in various cancer cell lines. A mechanism study in gastric carcinoma HGC-27 and MGC-803 cells revealed that B6a promoted cell cycle arrest and apoptosis, triggered protective autophagy, and suppressed the BMX/AKT/mTOR pathway. Notably, although B6a's bioavailability was extremely low, it still exhibited excellent antitumor potency in the HGC-27 xenograft model with high safety, demonstrating that B6a was a promising BMX inhibitor and worth further exploration.

22 Jul 2024·JCI Insight

Preclinical spheroid models identify BMX as a therapeutic target for metastatic MYCN nonamplified neuroblastoma

Article

Author: Cironi, Luisa ; Boulay, Gaylor ; Rivera, Miguel N. ; Riggi, Nicolò ; Colombo, Daniele Filippo ; Mühlethaler-Mottet, Annick ; Stamenkovic, Ivan ; Bardet, Anaïs Flore ; Broye, Liliane ; Sanalkumar, Rajendran ; Kuttler, Fabien ; Renella, Raffaele ; Sundaramoorthy, Santhoshkumar ; Turcatti, Gerardo ; Balmas Bourloud, Katia

The development of targeted therapies offers new hope for patients affected by incurable cancer. However, multiple challenges persist, notably in controlling tumor cell plasticity in patients with refractory and metastatic illness. Neuroblastoma (NB) is an aggressive pediatric malignancy originating from defective differentiation of neural crest-derived progenitors with oncogenic activity due to genetic and epigenetic alterations and remains a clinical challenge for high-risk patients. To identify critical genes driving NB aggressiveness, we performed combined chromatin and transcriptome analyses on matched patient-derived xenografts (PDXs), spheroids, and differentiated adherent cultures derived from metastatic MYCN nonamplified tumors. Bone marrow kinase on chromosome X (BMX) was identified among the most differentially regulated genes in PDXs and spheroids versus adherent models. BMX expression correlated with high tumor stage and poor patient survival and was crucial to the maintenance of the self-renewal and tumorigenic potential of NB spheroids. Moreover, BMX expression positively correlated with the mesenchymal NB cell phenotype, previously associated with increased chemoresistance. Finally, BMX inhibitors readily reversed this cellular state, increased the sensitivity of NB spheroids toward chemotherapy, and partially reduced tumor growth in a preclinical NB model. Altogether, our study identifies BMX as a promising innovative therapeutic target for patients with high-risk MYCN nonamplified NB.

15 Oct 2023·International journal of pharmaceutics

AI & experimental-based discovery and preclinical IND-enabling studies of selective BMX inhibitors for development of cancer therapeutics.

Article

Author: Khashan, Raed ; Jumaa, Mouhannad ; Nazzal, Sami ; Fayyad, Ahmed Abu ; Parupathi, Prashanth ; Elsanhoury, Rwan ; Kumar, Avinash ; Al-Fayoumi, Suliman ; Alasmari, Abdulaziz

The current work aims to design and provide a preliminary IND-enabling study of selective BMX inhibitors for cancer therapeutics development. BMX is an emerging target, more notably in oncological and immunological diseases. In this work, we have employed a predictive AI-based platform to design the selective inhibitors considering the novelty, IP prior protection, and drug-likeness properties. Furthermore, selected top candidates from the initial iteration of the design were synthesized and chemically characterized utilizing ¹H NMR and LC-MS. Employing a panel of biochemical (enzymatic) and cancer cell lines, the selected molecules were tested against these assays. In addition, we used artificial intelligence to predict and evaluate several critical IND-focused physicochemical and pharmacokinetics values of the selected molecules. A secondary objective of the current work was also to validate the sole role of BMX in animal models known to be mediated by BMX. More than 50 molecules were designed in the present study employing five novel discovered scaffolds. Two molecules were nominated for further IND-focused studies. Compound II showed promising in-vitro activity against BMX in both enzymatic assays compared to other kinases and in cancer cell lines with known BMX overexpression. Interestingly, compound II showed very favorable physicochemical and pharmacokinetics properties as predicted by the used platforms. The animal study further confirmed the sole role of BMX in the disease model. The current work provides promising data on a selective BMX inhibitor as a potential lead for therapeutics development, and the asset is currently in the optimization stage. Notably, the current study shows a framework for a combined approach employing both AI and experimentation that can be used by academic labs in their research programs to more streamline programs into IND-focused to be bridged easily for further clinical development with industrial partners.

100 Deals associated with BMX inhibitors(Zhengzhou University)

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Indication	Highest Phase	Country/Location	Organization	Date
Stomach Cancer	Discovery	China	Zhengzhou University	15 Feb 2025

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