Design, Synthesis, and Biological Evaluation of Dual Inhibitors of EGFR^L858R/T790M/ACK1 to Overcome Osimertinib Resistance in Nonsmall Cell Lung Cancers

Q1 · MEDICINE

Article

Author: Wang, Aoxue ; Li, Shutong ; Pei, Junping ; Wang, Guan ; Wu, Chengyong ; Wang, Xin ; Wang, Yuxi ; Yang, Panpan ; Liu, Jiaxi ; Shuai, Wen ; Ouyang, Liang

Activation of the alternative pathways and abnormal signaling transduction are frequently observed in third-generation EGFR-TKIs (epidermal growth factor receptor tyrosine kinase inhibitors)-resistant patients. Wherein, hyperphosphorylation of ACK1 contributes to EGFR-TKIs acquired resistance. Dual inhibition of EGFR^L858R/T790M and ACK1 might improve therapeutic efficacy and overcome resistance in lung cancers treatment. Here, we identified a EGFR^L858R/T790M/ACK1 dual-targeting compound 21a with aminoquinazoline scaffold, which showed excellent inhibitory activities against EGFR^L858R/T790M (IC₅₀ = 23 nM) and ACK1 (IC₅₀ = 263 nM). The cocrystal and docking analysis showed that 21a occupied the ATP binding pockets of EGFR^L858R/T790M and ACK1. Moreover, 21a showed potent antiproliferative activities against the H1975 cells, MCF-7 cells and osimertinib-resistant cells AZDR. Further, 21a showed significant antitumor effects and good safety in ADZR xenograft-bearing mice. Taken together, 21a was a potent dual inhibitor of EGFR^L858R/T790M/ACK1, which is deserved as a potential lead for overcoming acquired resistance to osimertinib during the EGFR-targeted therapy.

16 Jan 2024·ACS Omega

Structural Optimization and Biological Evaluation of Isoxazolo[5,4-d]pyrimidines as Selective Toll-Like Receptor 7 Agonists

Article

Author: Strašek Benedik, Nika ; Gobec, Stanislav ; Sosič, Izidor ; Sova, Matej ; Švajger, Urban ; Dolšak, Ana

Toll-like receptors (TLRs) are components of innate immunity that play a crucial role in several diseases, including chronic inflammatory and infectious diseases, autoimmune diseases, and cancer. In particular, TLR7 has been identified as a key player in the innate immune response against viral infections and small-molecule TLR7 agonists have shown potential for vaccine therapy, for treatment of asthma and allergies, and as anticancer drugs. Inspired by our previous discovery of selective TLR7 agonists, our goal was to develop and introduce a new chemotype of TLR7 agonists by replacing the quinazoline ring with a new heterocycle isoxazolo[5,4-d]pyrimidine. Here, we report design, optimized synthesis, and structure-activity relationship studies of a novel class of TLR7 agonists based on the 6-(trifluoromethyl)isoxazolo[5,4-d]pyrimidine-4-amine scaffold that demonstrate high selectivity and low micromolar potencies. The best-in-class agonist 21a, with an EC₅₀ value of 7.8 μM, also proved to be noncytotoxic and induced secretion of cytokines, including IL-1β, IL-12p70, IL-8, and TNF-α, indicating its potential to modulate the immune response.

01 Nov 2023·European Journal of Medicinal Chemistry

Design and optimization of selective and potent CDK9 inhibitors with flavonoid scaffold for the treatment of acute myeloid leukemia

Article

Author: Yu, Sixian ; Gong, Weihong ; Li, Zhiyu ; Zhao, Tengteng ; Tian, Yucheng ; Bian, Jinlei ; Wu, Tizhi ; Zhang, Jing ; Yu, Bin ; Wang, Jubo

Acute myeloid leukemia (AML) is a prevalent hematological tumor associated with a high morbidity and mortality rate. CDK9, functioning as a pivotal transcriptional regulator, facilitates transcriptional elongation through phosphorylation of RNA polymerase II, which further governs the protein levels of Mcl-1 and c-Myc. Therefore, CDK9 has been considered as a promising therapeutic target for AML treatment. Here, we present the design, synthesis, and evaluation of CDK9 inhibitors bearing a flavonoid scaffold. Among them, compound 21a emerged as a highly selective CDK9 inhibitor (IC₅₀ = 6.7 nM), exhibiting over 80-fold selectivity towards most other CDK family members and high kinase selectivity. In Mv4-11 cells, 21a effectively hindered cell proliferation (IC₅₀ = 60 nM) and induced apoptosis by down-regulating Mcl-1 and c-Myc. Notably, 21a demonstrated significant inhibition of tumor growth in the Mv4-11 xenograft tumor model. These findings indicate that compound 21a holds promise as a potential candidate for treating AML.

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Indication	Highest Phase	Country/Location	Organization	Date
Non-Small Cell Lung Cancer	Preclinical	China	Sichuan University	07 Feb 2024

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