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

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

doi:10.1021/acsmedchemlett.2c00490

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

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

Carcinogenesis and Chemoprevention

Research output: Contribution to journal › Article › peer-review

22 Scopus citations

Abstract

The use of small molecular modulators to target the guanine nucleotide exchange factor SOS1 has been demonstrated to be a promising strategy for the treatment of various KRAS-driven cancers. In the present study, we designed and synthesized a series of new SOS1 inhibitors with the pyrido[2,3-d]pyrimidin-7-one scaffold. One representative compound 8u showed comparable activities to the reported SOS1 inhibitor BI-3406 in both the biochemical assay and the 3-D cell growth inhibition assay. Compound 8u obtained good cellular activities against a panel of KRAS G12-mutated cancer cell lines and inhibited downstream ERK and AKT activation in MIA PaCa-2 and AsPC-1 cells. In addition, it displayed synergistic antiproliferative effects when used in combination with KRAS G12C or G12D inhibitors. Further modifications of the new compounds may give us a promising SOS1 inhibitor with favorable druglike properties for use in the treatment of KRAS-mutated patients.

Original language	English (US)
Pages (from-to)	183-190
Number of pages	8
Journal	ACS Medicinal Chemistry Letters
Volume	14
Issue number	2
DOIs	https://doi.org/10.1021/acsmedchemlett.2c00490
State	Published - Feb 9 2023

Bibliographical note

Funding Information:
We would like to thank Lingang Laboratory (LG-QS-202205-04 to T.X.; LG-QS-202204-01 to S.Z.), the National Natural Science Foundation of China (T2225002 to M.Z.), and the Natural Science Foundation of Shanghai (22ZR1474300 to S.Z.) for their financial support.

Publisher Copyright:
© 2023 American Chemical Society.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

KRAS mutation
SOS1 inhibitor
SOS1-KRAS interaction
combination therapy

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10.1021/acsmedchemlett.2c00490

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

abstract = "The use of small molecular modulators to target the guanine nucleotide exchange factor SOS1 has been demonstrated to be a promising strategy for the treatment of various KRAS-driven cancers. In the present study, we designed and synthesized a series of new SOS1 inhibitors with the pyrido[2,3-d]pyrimidin-7-one scaffold. One representative compound 8u showed comparable activities to the reported SOS1 inhibitor BI-3406 in both the biochemical assay and the 3-D cell growth inhibition assay. Compound 8u obtained good cellular activities against a panel of KRAS G12-mutated cancer cell lines and inhibited downstream ERK and AKT activation in MIA PaCa-2 and AsPC-1 cells. In addition, it displayed synergistic antiproliferative effects when used in combination with KRAS G12C or G12D inhibitors. Further modifications of the new compounds may give us a promising SOS1 inhibitor with favorable druglike properties for use in the treatment of KRAS-mutated patients.",

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author = "Meiying Liu and Guizhen Zhou and Wenhong Su and Yuejiao Gu and Mingshan Gao and Kun Wang and Ruifeng Huo and Yupeng Li and Zehui Zhou and Kaixian Chen and Mingyue Zheng and Sulin Zhang and Tianfeng Xu",

note = "Funding Information: We would like to thank Lingang Laboratory (LG-QS-202205-04 to T.X.; LG-QS-202204-01 to S.Z.), the National Natural Science Foundation of China (T2225002 to M.Z.), and the Natural Science Foundation of Shanghai (22ZR1474300 to S.Z.) for their financial support. Publisher Copyright: {\textcopyright} 2023 American Chemical Society.",

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AU - Liu, Meiying

AU - Zhou, Guizhen

AU - Su, Wenhong

AU - Gu, Yuejiao

AU - Gao, Mingshan

AU - Wang, Kun

AU - Huo, Ruifeng

AU - Li, Yupeng

AU - Zhou, Zehui

AU - Chen, Kaixian

AU - Zheng, Mingyue

AU - Zhang, Sulin

AU - Xu, Tianfeng

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PY - 2023/2/9

Y1 - 2023/2/9

N2 - The use of small molecular modulators to target the guanine nucleotide exchange factor SOS1 has been demonstrated to be a promising strategy for the treatment of various KRAS-driven cancers. In the present study, we designed and synthesized a series of new SOS1 inhibitors with the pyrido[2,3-d]pyrimidin-7-one scaffold. One representative compound 8u showed comparable activities to the reported SOS1 inhibitor BI-3406 in both the biochemical assay and the 3-D cell growth inhibition assay. Compound 8u obtained good cellular activities against a panel of KRAS G12-mutated cancer cell lines and inhibited downstream ERK and AKT activation in MIA PaCa-2 and AsPC-1 cells. In addition, it displayed synergistic antiproliferative effects when used in combination with KRAS G12C or G12D inhibitors. Further modifications of the new compounds may give us a promising SOS1 inhibitor with favorable druglike properties for use in the treatment of KRAS-mutated patients.

AB - The use of small molecular modulators to target the guanine nucleotide exchange factor SOS1 has been demonstrated to be a promising strategy for the treatment of various KRAS-driven cancers. In the present study, we designed and synthesized a series of new SOS1 inhibitors with the pyrido[2,3-d]pyrimidin-7-one scaffold. One representative compound 8u showed comparable activities to the reported SOS1 inhibitor BI-3406 in both the biochemical assay and the 3-D cell growth inhibition assay. Compound 8u obtained good cellular activities against a panel of KRAS G12-mutated cancer cell lines and inhibited downstream ERK and AKT activation in MIA PaCa-2 and AsPC-1 cells. In addition, it displayed synergistic antiproliferative effects when used in combination with KRAS G12C or G12D inhibitors. Further modifications of the new compounds may give us a promising SOS1 inhibitor with favorable druglike properties for use in the treatment of KRAS-mutated patients.

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KW - SOS1 inhibitor

KW - SOS1-KRAS interaction

KW - combination therapy

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

Abstract

Bibliographical note

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