Design, Synthesis, and Bioevaluation of Pyrido[2,3-<i>d</i>]pyrimidin-7-ones as Potent SOS1 Inhibitors

Zhou, Guangmin; Su, Wenhong; Gu, Yuejiao; Gao, Mingshan; Wang, Kun; Huo, Ruifeng; Li, Yupeng; Zhou, Zehui; Chen, Kaixian; Zheng, Mingyue; Zhang, Sulin; Xu, Tianfeng

doi:10.1021/acsmedchemlett.2c00490

Cited by 9 publications

(5 citation statements)

References 29 publications

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“…SOS1 is a well-known oncogenic transcriptional factor implicated in the initiation, progression, and metastasis of multiple tumors [ 47 , 48 ]. Development of inhibitors targeting SOS1 as potential therapeutic agents in cancer research [ 49 – 51 ]. However, the upstream regulatory mechanisms governing SOS1 connectivity in LCSLCs warrant further investigation.…”

Section: Discussionmentioning

confidence: 99%

DNMT1/miR-152-3p/SOS1 signaling axis promotes self-renewal and tumor growth of cancer stem-like cells derived from non-small cell lung cancer

Yuan,

Wang,

et al. 2024

Clin Epigenet

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Background CSLCs(Cancer stem cell-like cells), which are central to tumorigenesis, are intrinsically influenced by epigenetic modifications. This study aimed to elucidate the underlying mechanism involving the DNMT1/miR-152-3p/SOS1 axis in regulating the self-renewal and tumor growth of LCSLCs (lung cancer stem-like cells). Materials and methods Target genes of miR-152-3p were predicted using TargetScan Human 8.0. Self-renewal and tumor growth of LCSLC were compared in suspension-cultured non-small cell lung cancer (NSCLC) cell lines H460 and A549 cell-derived globe cells. Functional effects of the DNMT1/miR-152-3p/SOS1 axis were assessed through gain-of-function experiments in vitro and in vivo. Additionally, luciferase reporter assays were employed to analyze the interaction among DNMT1, miR-152-3p, and SOS1. Results Our findings highlight a negative interaction between DNMT1 and miR-152-3p, resulting in reduced miR-152-3p level. This, in turn, leads to the alleviation of the inhibitory effect of miR-152-3p on the target gene SOS1, ultimately activating SOS1 and playing an essential role in self-renewal and tumor growth of LCSLC. However, the alteration of SOS1 does not affect DNMT1/miR-152-3p regulation. Therefore, it is reasonable to infer that the DNMT1/miR-152-3p negative feedback loop critically sustains self-renewal and tumor growth of LCSLC through SOS1. Conclusions This study reveals a novel mechanism underpinning self-renewal and tumor growth of CSLC (cancer stem cell) in NSCLC and identifies potential therapeutic targets for NSCLC treatment.

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Section: Discussionmentioning

confidence: 99%

DNMT1/miR-152-3p/SOS1 signaling axis promotes self-renewal and tumor growth of cancer stem-like cells derived from non-small cell lung cancer

Yuan,

Wang,

et al. 2024

Clin Epigenet

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“…32 Further structural analysis revealed that in contrast to known amino quinazoline inhibitors, those eight hits all have a pyrido pyrimidine scaffold, which did not appear in the training set. This structure has been designed and synthesized recently by Liu et al 35 as a novel potent SOS1 inhibitor pharmacophore. Furthermore, we compare the structural similarity of I-37 and I-49 with the training set based on the Tanimoto coefficient.…”

Section: Rsc Medicinal Chemistry Research Articlementioning

confidence: 99%

Discovery of novel SOS1 inhibitors using machine learning

Duo,

Chen,

Liu

et al. 2024

RSC Med. Chem.

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“…The Xu group recently disclosed a scaffold-hopping strategy to identify potent SOS1 inhibitors 40 with a privileged pyridopyrimidinone core (Figure 13). 97 They first explored the SAR of the R 1 substituent and found that acetylpiperidine was optimal. The replacement of R 1 with smaller hydrogen, amine, or acetylamine resulted in the loss of potency.…”

Section: Sos1 Inhibitorsmentioning

confidence: 99%

Development of Son of Sevenless Homologue 1 (SOS1) Modulators To Treat Cancers by Regulating RAS Signaling

et al. 2023

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Son of sevenless homologue 1 (SOS1) protein is universally expressed in cells and plays an important role in the RAS signaling pathway. Specifically, this protein interacts with RAS in response to upstream stimuli to promote guanine nucleotide exchange in RAS and activates the downstream signaling pathways. Thus, targeting SOS1 is a new approach for treating RAS-driven cancers. In this Perspective, we briefly summarize the structural and functional aspects of SOS1 and focus on recent advances in the discovery of activators, inhibitors, and PROTACs that target SOS1. This review aims to provide a timely and updated overview on the strategies for targeting SOS1 in cancer therapy.

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Design, Synthesis, and Bioevaluation of Pyrido[2,3-d]pyrimidin-7-ones as Potent SOS1 Inhibitors

Cited by 9 publications

References 29 publications

DNMT1/miR-152-3p/SOS1 signaling axis promotes self-renewal and tumor growth of cancer stem-like cells derived from non-small cell lung cancer

DNMT1/miR-152-3p/SOS1 signaling axis promotes self-renewal and tumor growth of cancer stem-like cells derived from non-small cell lung cancer

Discovery of novel SOS1 inhibitors using machine learning

Development of Son of Sevenless Homologue 1 (SOS1) Modulators To Treat Cancers by Regulating RAS Signaling

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