Novel Small Molecules Capable of Blocking mtRAS-Signaling Pathway
RAS mutants are involved in approximately 30% of all human cancers and have been regarded as undruggable targets owing to relatively smooth protein surface and obscure binding pockets. In our previous study, we have demonstrated that GNF-7, a multi-targeted kinase inhibitor, possesses potent anti-pr...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2021-12-01
|
| Series: | Frontiers in Oncology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2021.768022/full |
| _version_ | 1818400424395276288 |
|---|---|
| author | Namkyoung Kim Namkyoung Kim Injae Shin Injae Shin Younghoon Kim Younghoon Kim Eunhye Jeon Jiwon Lee Chaeyoung Lee Yunju Nam Yunju Nam Sumin Lee Eunhye Ju Chan Kim Woolim Son SeongShick Ryu SeongShick Ryu Minjoo Ko Taebo Sim Taebo Sim |
| author_facet | Namkyoung Kim Namkyoung Kim Injae Shin Injae Shin Younghoon Kim Younghoon Kim Eunhye Jeon Jiwon Lee Chaeyoung Lee Yunju Nam Yunju Nam Sumin Lee Eunhye Ju Chan Kim Woolim Son SeongShick Ryu SeongShick Ryu Minjoo Ko Taebo Sim Taebo Sim |
| author_sort | Namkyoung Kim |
| collection | DOAJ |
| description | RAS mutants are involved in approximately 30% of all human cancers and have been regarded as undruggable targets owing to relatively smooth protein surface and obscure binding pockets. In our previous study, we have demonstrated that GNF-7, a multi-targeted kinase inhibitor, possesses potent anti-proliferative activity against Ba/F3 cells transformed with NRAS-G12D. Based on our further analysis using Ba/F3 cells transformed with mtRAS, we discovered a series of pyrimido[4,5-d]pyrimidin-2-one analogues as mtRAS-signaling pathway blockers. In addition, our efforts expanded the assessment to cancer cells with mtRAS, which revealed that these substances are also capable of strongly suppressing the proliferation of various cancer cells harboring KRAS-G12D (AsPC-1), KRAS-G12V (SW480, DU-145), KRAS-G12C (H358), KRAS-G13D (MDA-MB-231), KRAS-Q61L (HT-29), and NRAS-Q61L (OCI-AML3). We herein report novel and potent mtRAS-signaling pathway blockers, SIJ1795 and SIJ1772, possessing 2 to 10-fold increased anti-proliferative activities compared to those of GNF-7 on cancer cells harboring mtRAS as well as on Ba/F3 cells transformed with mtRAS. Both SIJ1795 and SIJ1772 attenuate phosphorylation of RAS downstream molecules (AKT and MEK) and induce apoptosis and G0/G1 cell cycle arrest on cancer cells with mtRAS. Moreover, both substances substantially suppress the migration, invasion, and colony formation of cancer cells harboring mtRAS. Taken together, this study led us to identification of SIJ1795 and SIJ1772 capable of strongly inhibiting mtRAS-signaling pathway on cancer cells harboring mtRAS. |
| first_indexed | 2024-12-14T07:36:21Z |
| format | Article |
| id | doaj.art-ab077dce29e646abaf028b086d8ff2d9 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-14T07:36:21Z |
| publishDate | 2021-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-ab077dce29e646abaf028b086d8ff2d92022-12-21T23:11:11ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2021-12-011110.3389/fonc.2021.768022768022Novel Small Molecules Capable of Blocking mtRAS-Signaling PathwayNamkyoung Kim0Namkyoung Kim1Injae Shin2Injae Shin3Younghoon Kim4Younghoon Kim5Eunhye Jeon6Jiwon Lee7Chaeyoung Lee8Yunju Nam9Yunju Nam10Sumin Lee11Eunhye Ju12Chan Kim13Woolim Son14SeongShick Ryu15SeongShick Ryu16Minjoo Ko17Taebo Sim18Taebo Sim19KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, South KoreaSeverance Biomedical Science Institute, Graduate School of Medical Science, Yonsei University College of Medicine, Seoul, South KoreaKU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, South KoreaSeverance Biomedical Science Institute, Graduate School of Medical Science, Yonsei University College of Medicine, Seoul, South KoreaKU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, South KoreaSeverance Biomedical Science Institute, Graduate School of Medical Science, Yonsei University College of Medicine, Seoul, South KoreaSeverance Biomedical Science Institute, Graduate School of Medical Science, Yonsei University College of Medicine, Seoul, South KoreaSeverance Biomedical Science Institute, Graduate School of Medical Science, Yonsei University College of Medicine, Seoul, South KoreaSeverance Biomedical Science Institute, Graduate School of Medical Science, Yonsei University College of Medicine, Seoul, South KoreaKU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, South KoreaSeverance Biomedical Science Institute, Graduate School of Medical Science, Yonsei University College of Medicine, Seoul, South KoreaSeverance Biomedical Science Institute, Graduate School of Medical Science, Yonsei University College of Medicine, Seoul, South KoreaKU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, South KoreaSeverance Biomedical Science Institute, Graduate School of Medical Science, Yonsei University College of Medicine, Seoul, South KoreaSeverance Biomedical Science Institute, Graduate School of Medical Science, Yonsei University College of Medicine, Seoul, South KoreaKU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, South KoreaSeverance Biomedical Science Institute, Graduate School of Medical Science, Yonsei University College of Medicine, Seoul, South KoreaSeverance Biomedical Science Institute, Graduate School of Medical Science, Yonsei University College of Medicine, Seoul, South KoreaKU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, South KoreaSeverance Biomedical Science Institute, Graduate School of Medical Science, Yonsei University College of Medicine, Seoul, South KoreaRAS mutants are involved in approximately 30% of all human cancers and have been regarded as undruggable targets owing to relatively smooth protein surface and obscure binding pockets. In our previous study, we have demonstrated that GNF-7, a multi-targeted kinase inhibitor, possesses potent anti-proliferative activity against Ba/F3 cells transformed with NRAS-G12D. Based on our further analysis using Ba/F3 cells transformed with mtRAS, we discovered a series of pyrimido[4,5-d]pyrimidin-2-one analogues as mtRAS-signaling pathway blockers. In addition, our efforts expanded the assessment to cancer cells with mtRAS, which revealed that these substances are also capable of strongly suppressing the proliferation of various cancer cells harboring KRAS-G12D (AsPC-1), KRAS-G12V (SW480, DU-145), KRAS-G12C (H358), KRAS-G13D (MDA-MB-231), KRAS-Q61L (HT-29), and NRAS-Q61L (OCI-AML3). We herein report novel and potent mtRAS-signaling pathway blockers, SIJ1795 and SIJ1772, possessing 2 to 10-fold increased anti-proliferative activities compared to those of GNF-7 on cancer cells harboring mtRAS as well as on Ba/F3 cells transformed with mtRAS. Both SIJ1795 and SIJ1772 attenuate phosphorylation of RAS downstream molecules (AKT and MEK) and induce apoptosis and G0/G1 cell cycle arrest on cancer cells with mtRAS. Moreover, both substances substantially suppress the migration, invasion, and colony formation of cancer cells harboring mtRAS. Taken together, this study led us to identification of SIJ1795 and SIJ1772 capable of strongly inhibiting mtRAS-signaling pathway on cancer cells harboring mtRAS.https://www.frontiersin.org/articles/10.3389/fonc.2021.768022/fullRAS signaling pathwaycancers with mtRASmutated RASRAS signaling blockermulti-targeted kinase inhibitorGNF-7 |
| spellingShingle | Namkyoung Kim Namkyoung Kim Injae Shin Injae Shin Younghoon Kim Younghoon Kim Eunhye Jeon Jiwon Lee Chaeyoung Lee Yunju Nam Yunju Nam Sumin Lee Eunhye Ju Chan Kim Woolim Son SeongShick Ryu SeongShick Ryu Minjoo Ko Taebo Sim Taebo Sim Novel Small Molecules Capable of Blocking mtRAS-Signaling Pathway Frontiers in Oncology RAS signaling pathway cancers with mtRAS mutated RAS RAS signaling blocker multi-targeted kinase inhibitor GNF-7 |
| title | Novel Small Molecules Capable of Blocking mtRAS-Signaling Pathway |
| title_full | Novel Small Molecules Capable of Blocking mtRAS-Signaling Pathway |
| title_fullStr | Novel Small Molecules Capable of Blocking mtRAS-Signaling Pathway |
| title_full_unstemmed | Novel Small Molecules Capable of Blocking mtRAS-Signaling Pathway |
| title_short | Novel Small Molecules Capable of Blocking mtRAS-Signaling Pathway |
| title_sort | novel small molecules capable of blocking mtras signaling pathway |
| topic | RAS signaling pathway cancers with mtRAS mutated RAS RAS signaling blocker multi-targeted kinase inhibitor GNF-7 |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2021.768022/full |
| work_keys_str_mv | AT namkyoungkim novelsmallmoleculescapableofblockingmtrassignalingpathway AT namkyoungkim novelsmallmoleculescapableofblockingmtrassignalingpathway AT injaeshin novelsmallmoleculescapableofblockingmtrassignalingpathway AT injaeshin novelsmallmoleculescapableofblockingmtrassignalingpathway AT younghoonkim novelsmallmoleculescapableofblockingmtrassignalingpathway AT younghoonkim novelsmallmoleculescapableofblockingmtrassignalingpathway AT eunhyejeon novelsmallmoleculescapableofblockingmtrassignalingpathway AT jiwonlee novelsmallmoleculescapableofblockingmtrassignalingpathway AT chaeyounglee novelsmallmoleculescapableofblockingmtrassignalingpathway AT yunjunam novelsmallmoleculescapableofblockingmtrassignalingpathway AT yunjunam novelsmallmoleculescapableofblockingmtrassignalingpathway AT suminlee novelsmallmoleculescapableofblockingmtrassignalingpathway AT eunhyeju novelsmallmoleculescapableofblockingmtrassignalingpathway AT chankim novelsmallmoleculescapableofblockingmtrassignalingpathway AT woolimson novelsmallmoleculescapableofblockingmtrassignalingpathway AT seongshickryu novelsmallmoleculescapableofblockingmtrassignalingpathway AT seongshickryu novelsmallmoleculescapableofblockingmtrassignalingpathway AT minjooko novelsmallmoleculescapableofblockingmtrassignalingpathway AT taebosim novelsmallmoleculescapableofblockingmtrassignalingpathway AT taebosim novelsmallmoleculescapableofblockingmtrassignalingpathway |