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.
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).
