TNG908 is a brain-penetrant, MTA-cooperative PRMT5 inhibitor developed for the treatment of MTAP-deleted cancers
ABSTRACT: TNG908 is a clinical stage PRMT5 inhibitor with an MTA-cooperative binding mechanism designed to leverage the synthetic lethal interaction between PRMT5 inhibition and MTAP deletion. MTAP deletion occurs in 10–15 % of all human cancer representing multiple histologies. MTA is a negative re...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-02-01
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| Series: | Translational Oncology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1936523324003905 |
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| author | Kimberly J. Briggs Kevin M. Cottrell Matthew R. Tonini Alice Tsai Minjie Zhang Douglas A. Whittington Wenhai Zhang Steven A. Lombardo Satoshi Yoda Erik W. Wilker Samuel R. Meier Yi Yu Teng Teng Alan Huang John P. Maxwell |
| author_facet | Kimberly J. Briggs Kevin M. Cottrell Matthew R. Tonini Alice Tsai Minjie Zhang Douglas A. Whittington Wenhai Zhang Steven A. Lombardo Satoshi Yoda Erik W. Wilker Samuel R. Meier Yi Yu Teng Teng Alan Huang John P. Maxwell |
| author_sort | Kimberly J. Briggs |
| collection | DOAJ |
| description | ABSTRACT: TNG908 is a clinical stage PRMT5 inhibitor with an MTA-cooperative binding mechanism designed to leverage the synthetic lethal interaction between PRMT5 inhibition and MTAP deletion. MTAP deletion occurs in 10–15 % of all human cancer representing multiple histologies. MTA is a negative regulator of PRMT5 that accumulates as a result of MTAP deletion. In this study, we demonstrate that TNG908 selectively binds the PRMT5·MTA complex driving selective inhibition of PRMT5 in MTAP-null cancers, a mechanism that creates a large therapeutic index relative to first generation PRMT5 inhibitors that have alternative binding mechanisms that are not tumor-selective. Strong preclinical activity in multiple MTAP-deleted xenograft models, as well as demonstrated brain penetrance in preclinical models, support the potential for histology-agnostic clinical development of TNG908 in MTAP-deleted solid tumors, including CNS malignancies. TNG908 is being tested clinically in patients with MTAP-deleted tumors, including glioblastoma, in a Phase I/II clinical trial (NCT05275478). |
| format | Article |
| id | doaj-art-4696adece42546adac2fb883892bfaec |
| institution | Kabale University |
| issn | 1936-5233 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Translational Oncology |
| spelling | doaj-art-4696adece42546adac2fb883892bfaec2025-01-22T05:41:32ZengElsevierTranslational Oncology1936-52332025-02-0152102264TNG908 is a brain-penetrant, MTA-cooperative PRMT5 inhibitor developed for the treatment of MTAP-deleted cancersKimberly J. Briggs0Kevin M. Cottrell1Matthew R. Tonini2Alice Tsai3Minjie Zhang4Douglas A. Whittington5Wenhai Zhang6Steven A. Lombardo7Satoshi Yoda8Erik W. Wilker9Samuel R. Meier10Yi Yu11Teng Teng12Alan Huang13John P. Maxwell14Corresponding author.; Tango Therapeutics, Tango Therapeutics, 201 Brookline Avenue, Boston, 02215, MA, United StatesTango Therapeutics, Tango Therapeutics, 201 Brookline Avenue, Boston, 02215, MA, United StatesTango Therapeutics, Tango Therapeutics, 201 Brookline Avenue, Boston, 02215, MA, United StatesTango Therapeutics, Tango Therapeutics, 201 Brookline Avenue, Boston, 02215, MA, United StatesTango Therapeutics, Tango Therapeutics, 201 Brookline Avenue, Boston, 02215, MA, United StatesTango Therapeutics, Tango Therapeutics, 201 Brookline Avenue, Boston, 02215, MA, United StatesTango Therapeutics, Tango Therapeutics, 201 Brookline Avenue, Boston, 02215, MA, United StatesTango Therapeutics, Tango Therapeutics, 201 Brookline Avenue, Boston, 02215, MA, United StatesTango Therapeutics, Tango Therapeutics, 201 Brookline Avenue, Boston, 02215, MA, United StatesTango Therapeutics, Tango Therapeutics, 201 Brookline Avenue, Boston, 02215, MA, United StatesTango Therapeutics, Tango Therapeutics, 201 Brookline Avenue, Boston, 02215, MA, United StatesTango Therapeutics, Tango Therapeutics, 201 Brookline Avenue, Boston, 02215, MA, United StatesTango Therapeutics, Tango Therapeutics, 201 Brookline Avenue, Boston, 02215, MA, United StatesTango Therapeutics, Tango Therapeutics, 201 Brookline Avenue, Boston, 02215, MA, United StatesTango Therapeutics, Tango Therapeutics, 201 Brookline Avenue, Boston, 02215, MA, United StatesABSTRACT: TNG908 is a clinical stage PRMT5 inhibitor with an MTA-cooperative binding mechanism designed to leverage the synthetic lethal interaction between PRMT5 inhibition and MTAP deletion. MTAP deletion occurs in 10–15 % of all human cancer representing multiple histologies. MTA is a negative regulator of PRMT5 that accumulates as a result of MTAP deletion. In this study, we demonstrate that TNG908 selectively binds the PRMT5·MTA complex driving selective inhibition of PRMT5 in MTAP-null cancers, a mechanism that creates a large therapeutic index relative to first generation PRMT5 inhibitors that have alternative binding mechanisms that are not tumor-selective. Strong preclinical activity in multiple MTAP-deleted xenograft models, as well as demonstrated brain penetrance in preclinical models, support the potential for histology-agnostic clinical development of TNG908 in MTAP-deleted solid tumors, including CNS malignancies. TNG908 is being tested clinically in patients with MTAP-deleted tumors, including glioblastoma, in a Phase I/II clinical trial (NCT05275478).http://www.sciencedirect.com/science/article/pii/S1936523324003905PRMT5MTAPMTA-cooperativesynthetic lethalitycollateral lethality |
| spellingShingle | Kimberly J. Briggs Kevin M. Cottrell Matthew R. Tonini Alice Tsai Minjie Zhang Douglas A. Whittington Wenhai Zhang Steven A. Lombardo Satoshi Yoda Erik W. Wilker Samuel R. Meier Yi Yu Teng Teng Alan Huang John P. Maxwell TNG908 is a brain-penetrant, MTA-cooperative PRMT5 inhibitor developed for the treatment of MTAP-deleted cancers Translational Oncology PRMT5 MTAP MTA-cooperative synthetic lethality collateral lethality |
| title | TNG908 is a brain-penetrant, MTA-cooperative PRMT5 inhibitor developed for the treatment of MTAP-deleted cancers |
| title_full | TNG908 is a brain-penetrant, MTA-cooperative PRMT5 inhibitor developed for the treatment of MTAP-deleted cancers |
| title_fullStr | TNG908 is a brain-penetrant, MTA-cooperative PRMT5 inhibitor developed for the treatment of MTAP-deleted cancers |
| title_full_unstemmed | TNG908 is a brain-penetrant, MTA-cooperative PRMT5 inhibitor developed for the treatment of MTAP-deleted cancers |
| title_short | TNG908 is a brain-penetrant, MTA-cooperative PRMT5 inhibitor developed for the treatment of MTAP-deleted cancers |
| title_sort | tng908 is a brain penetrant mta cooperative prmt5 inhibitor developed for the treatment of mtap deleted cancers |
| topic | PRMT5 MTAP MTA-cooperative synthetic lethality collateral lethality |
| url | http://www.sciencedirect.com/science/article/pii/S1936523324003905 |
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