Gintemetostat

(1S)-1-[(3R)-3-amino-4′-[(6-amino-9H-purin-9-yl)methyl]-6′-(2,5-difluoro-4-methoxyphenyl)-3,4,5,6-tetrahydro-2H-[1,3′-bipyridin]-3-yl]-2,2-difluoroethan1-ol
antineoplastic, KTX 1001, NSD2 inhibitor 161, A48CGJ5UQM

CAS 2604513-16-6

MF C25H26F4N8O2 MW 546.5 g/mol

(S)-1-((R)-3-Amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol

Gintemetostat (also known as KTX-1001) is a first-in-class, orally administered small molecule being developed to treat relapsed and refractory multiple myeloma. It works as a selective inhibitor of NSD2 (also known as MMSET), targeting the epigenetic drivers of high-risk cancers.

How it Works

• Mechanism: Gintemetostat selectively binds to the catalytic SET domain of the NSD2 enzyme.
• Effect: By blocking this enzyme, it downregulates oncogenic signaling, decreases cancer cell growth, and can enhance T-cell activation against the tumor.

Target Patient Population

• High-Risk Myeloma: The drug focuses heavily on patients harboring the t(4;14) translocation, a genetic alteration found in 10-15% of patients that often causes aggressive relapses.
• Refractory Cases: It has shown notable single-agent activity in heavily pretreated patients who have exhausted standard-of-care, triple-class refractory treatment options.

Current Clinical Status

• Phase 1 Trial: Early data from phase 1 trials (such as NCT05651932) showed the drug has manageable safety profiles and offers clinical benefit (ranging from stable disease to very good partial response) in patients with aggressive, hard-to-treat multiple myeloma.
• Future Developments: Researchers are expanding studies to pair gintemetostat with other standard myeloma treatments, such as proteasome inhibitors and CELMoDs, to create stronger synergistic anti-cancer effects.

Gintemetostat is an orally available small molecule inhibitor of the histone-lysine N-methyltransferase nuclear receptor-binding SET domain protein 2 (NSD2; MMSET; WHSC1), with potential antineoplastic activity. Upon oral administration, gintemetostat selectively targets and binds to NSD2, and inhibits its catalytic activity and the mono- and di-methylation of histone H3 lysine 36 (H3K36). This modulates the expression of genes involved in cellular processes including cellular proliferation, which may lead to decreased growth of cancer cells. NSD2, a member of the NSD family of histone lysine methyltransferase enzymes that catalyzes the mono- and di-methylation of H3K36, is overexpressed and dysregulated in many types of cancers.

SYN

Discovery of a Highly Potent and Selective Inhibitor Targeting Protein Lysine Methyltransferase NSD2

Publication Name: Journal of Medicinal Chemistry

Publication Date: 2024-09-04

PMID: 39230932

DOI: 10.1021/acs.jmedchem.4c00639

SYN

US11420970, Example 161

PAT

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=ABFD7F90C50A184D0F39C0868B951358.wapp1nC?docId=US465978956&_cid=P12-MQ0AWU-11351-1

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021028854&_cid=P12-MQ0AZT-13511-1

Example 160 and Example 161: (R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6- (2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol and (S)-1-((R)-3- amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3- yl)piperidin-3-yl)-2,2-difluoroethan-1-ol

To a solution of tert-butyl (tert-butoxycarbonyl)(9-((5-(3-((tert-butoxycarbonyl)amino)-3-(2,2- difluoro-1-hydroxyethyl)piperidin-1-yl)-2-(2,5-difluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H- purin-6-yl)carbamate (Intermediate 160-3) (200 mg, 0.237 mmol) in DCM (18 mL), was added TFA (36 mL), and the reaction mixrture was stirred at rt for 30 min under N₂ atmosphere. The reaction mixture was concentrated in vacuo to give the crude product. The crude product was purifed by Pre-HPLC and SFC to afford (R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9- yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol (Example 160) and (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4- methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol (Example 161).

Example 160: ¹H NMR (400 MHz, CD₃OD) d ppm 8.48 (s, 1H), 8.20 (d, J = 1.6 Hz, 2H), 7.58 (dd, J = 12.2, 7.3 Hz, 1H), 7.11 (d, J = 1.3 Hz, 1H), 6.90 (dd, J = 12.6, 7.1 Hz, 1H), 6.06 (td, J = 55.1, 3.9 Hz, 1H), 5.67 (s, 2H), 3.87 (s, 3H), 3.75 – 3.58 (m, 1H), 3.25 – 2.75 (m, 4H), 2.26 – 1.60 (m, 4H). LC-MS: [M+H]⁺ = 547.2, 548.2.

Example 161: ¹H NMR (400MHz, CD₃OD) d = 8.51 – 8.44 (m, 1H), 8.24 – 8.16 (m, 2H), 7.62 – 7.48 (m, 1H), 7.03 (s, 1H), 6.93 – 6.79 (m, 1H), 6.25 – 5.86 (m, 1H), 5.71 – 5.59 (m, 2H), 4.00 (m, 1H), 3.88 – 3.80 (m, 3H), 3.28 – 2.87 (m, 4H), 1.99 – 1.56 (m, 4H). LC-MS: [M+H]⁺ =547.4.

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////////////gintemetostat, ANAX LABS, antineoplastic, KTX 1001, NSD2 inhibitor 161, A48CGJ5UQM