Cyclin-dependent kinases 12 and 13 (CDK12/13) safeguard genomic integrity by preferentially regulating gene expression in the DNA damage response (DDR). The CDK12/13-mediated upregulation of DDR genes and pathways significantly contributes to both tumorigenesis and the development of resistance to antitumor therapies. Thus, the functional inhibition of CDK12/13 offers an attractive strategy to combat carcinogenesis, particularly for refractory and treatment-resistant cancers.
View Article and Find Full Text PDFProtein tyrosine phosphatases PTPN2 and PTPN1 (also known as PTP1B) have been implicated in a number of intracellular signaling pathways of immune cells. The inhibition of PTPN2 and PTPN1 has emerged as an attractive approach to sensitize T cell anti-tumor immunity. Two small molecule inhibitors have been entered the clinic.
View Article and Find Full Text PDFInhibition of the low fidelity DNA polymerase Theta (Polθ) is emerging as an attractive, synthetic-lethal antitumor strategy in BRCA-deficient tumors. Here we report the AI-enabled development of 3-hydroxymethyl-azetidine derivatives as a novel class of Polθ inhibitors featuring central scaffolding rings. Structure-based drug design first identified A7 as a lead compound, which was further optimized to the more potent derivative B3 and the metabolically stable deuterated compound C1.
View Article and Find Full Text PDFWe previously described the discovery of a novel indole series compounds as oral SERD for ER positive breast cancer treatment. Further SAR exploration focusing on substitutions on indole moiety of compound 12 led to the discovery of a clinical candidate LX-039. We report herein its profound anti-tumor activity, desirable ER antagonistic characteristics combined with favorable pharmacokinetic and preliminary safety properties.
View Article and Find Full Text PDFWith the rapid development of the Internet of Things (IoT) and the emergence of 5G, traditional silicon-based electronics no longer fully meet market demands such as nonplanar application scenarios due to mechanical mismatch. This provides unprecedented opportunities for flexible electronics that bypass the physical rigidity through the introduction of flexible materials. In recent decades, biological materials with outstanding biocompatibility and biodegradability, which are considered some of the most promising candidates for next-generation flexible electronics, have received increasing attention, e.
View Article and Find Full Text PDFMost estrogen receptor positive (ER +) breast cancers depend on ER signaling pathway to develop. Clinical application of SERD fulvestrant effectively degraded ER, blocked its function and prolonged progression free survival of ER + breast cancer patients. However, current SERD suffers from limited bioavailability, therefore is given as intramuscular (IM) injection.
View Article and Find Full Text PDFIn this paper, we describe the discovery and optimization of a series of noncovalent reversible epidermal growth factor receptor inhibitors of EGFR. One of the most promising compounds, , inhibited the enzymatic activity of EGFR with an IC value of 2.2 nM.
View Article and Find Full Text PDFFirst-generation epidermal growth factor receptor (EGFR) inhibitors, gefitinib and erlotinib, have achieved initially marked clinical efficacy for nonsmall cell lung cancer (NSCLC) patients with EGFR activating mutations. However, their clinical benefit was limited by the emergence of acquired resistance mutations. In most cases (approximately 60%), the resistance was caused by the secondary EGFR T790M gatekeeper mutation.
View Article and Find Full Text PDFEpidermal growth factor receptor (EGFR) T790M acquired drug-resistance mutation has become a major clinical challenge for the therapy of non-small cell lung cancer. Here, we applied a structure-guided approach on the basis of the previous reported EGFR inhibitor (compound 9), and designed a series of C4-alkyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one derivatives as novel mutant-selective EGFR inhibitors. Finally, the most representative compound 20a was identified, which showed high selectivity at both enzymatic and cellular levels against EGFR (H1975 cell lines) over EGFR (A431 cell lines).
View Article and Find Full Text PDFNovel carbazole aminoalcohols were designed and synthesized as anticancer agents. Among them, alkylamine-chain-substituted compounds showed the most promising antiproliferative activity, with IC values in the single-digit micromolar range against two human tumor cell lines. Topoisomerase I (topo I) is likely to be one of the targets of these compounds.
View Article and Find Full Text PDFEGFR-targeted inhibitors (gefitinib and erlotinib) provided an effective strategy for the treatment of non-small-cell lung cancer. However, the EGFR T790M secondary mutation has become a leading cause of clinically acquired resistance to these agents. Herein, on the basis of the previously reported irreversible EGFR inhibitor (compound 9), we present a structure-based design approach, which is rationalized via analyzing its binding model and comparing the differences of gatekeeper pocket between the T790M mutant and wild-type (WT) EGFR kinases.
View Article and Find Full Text PDFFLT3 has been validated as a therapeutic target for the treatment of acute myeloid leukemia (AML). In this paper, we describe for the first time, pteridin-7(8H)-one as a scaffold for potent FLT3 inhibitors derived from structural optimizations on irreversible EGFR inhibitors. The representative inhibitor (31) demonstrates single-digit nanomolar inhibition against FLT3 and subnanomolar KD for drug-resistance FLT3 mutants.
View Article and Find Full Text PDFSulfhydryl-containing proteins play critical roles in various physiological and biological processes, and the activities of those proteins have been reported to be susceptible to thiol oxidation. Therefore, the development of protein thiol target fluorescent probe is highly desirable. In the present work, a biotinylated coumarin fluorescence "off-on" probe SQ for selectively detecting protein thiols in biotin receptor-positive cancer cells was designed with a 2,4-dinitrobenzenesulfony as the thiol receptor.
View Article and Find Full Text PDFTwo biotinylated coumarin-based fluorescent probes SPS3 and RC3 were designed for differentiating between structurally similar proteins streptavidin (SA) and avidin (AV). A substituted phenyl group is introduced onto SPS3, which may quench the fluorescence through twist intramolecular charge transfer (TICT). The fluorescence of SPS3 is turned on, by restraining the TICT process, when the fluorophore is buried at the surface of SA.
View Article and Find Full Text PDFTaking the emergence of drug resistance and lack of effective antimalarial vaccines into consideration, it is of significant importance to develop novel antimalarial agents for the treatment of malaria. Herein, we elucidated the discovery and structure-activity relationships of a series of dihydrothiophenone derivatives as novel specific inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH). The most promising compound, 50, selectively inhibited PfDHODH (IC50 = 6 nM, with >14,000-fold species-selectivity over hDHODH) and parasite growth in vitro (IC50 = 15 and 18 nM against 3D7 and Dd2 cells, respectively).
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