NX-2127

• CAT Number: I041300
• CAS Number: 2416131-46-7
• Molecular Formula: C39H45N9O5
• Molecular Weight: 719.83
• Purity: ≥95%
• Synonyms: 3-[4-[1-[[(3S)-1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]pyrrolidin-3-yl]methyl]piperidin-4-yl]anilino]-5-piperidin-1-ylpyrazine-2-carboxamide
• InChI: InChI=1S/C39H45N9O5/c40-35(50)34-36(43-32(21-41-34)46-15-2-1-3-16-46)42-27-6-4-25(5-7-27)26-13-17-45(18-14-26)22-24-12-19-47(23-24)28-8-9-29-30(20-28)39(53)48(38(29)52)31-10-11-33(49)44-37(31)51/h4-9,20-21,24,26,31H,1-3,10-19,22-23H2,(H2,40,50)(H,42,43)(H,44,49,51)/t24-,31?/m0/s1
• InChIKey: XLWJWCMQMBVNSG-ACXKHFGCSA-N
• SMILES: C1CCN(CC1)C2=CN=C(C(=N2)NC3=CC=C(C=C3)C4CCN(CC4)CC5CCN(C5)C6=CC7=C(C=C6)C(=O)N(C7=O)C8CCC(=O)NC8=O)C(=O)N

NX-2127 is an orally and potent BTK inhibitor, inducing degradation of the mutated BTKC481S in cells. NX-2127 inhibits proliferation of BTKC481S mutant TMD8 cells, more effectively than Ibrutinib (HY-10997). NX-2127 catalyzes the degradation of Ikaros (IKZF1) and Aiolos (IKZF3) with of 25 nM and 54 nM, respectively. NX-2127 stimulates T cell activation and increases IL-2 production in primary human T Cells[1][2].
NX-2127 inhibits proliferation of BTK-C481S mutant TMD8 cells with an EC50 value <30 nM[1]. NX-2127 increases IL-2 production in primary human T Cells[1].
NX-2127 (1 mg/kg; po; once daily for 14 days) demonstrates potent degradation of BTK in cynomolgus monkeys in vivo[1].
NX-2127 (po) leads to dose-proportional exposure in plasma and BTK degradation to <10% of baseline levels in circulating and splenic B cells[1]. NX-2127 results in superior tumor growth inhibition (TGI) in both WT TMD8 and C481S mutant xenograft models in mouse[1].

Reference

[1]. Robbins D W, et al. Nx-2127, a degrader of BTK and IMiD neosubstrates, for the treatment of B-cell malignancies. Blood, 2020, 136: 34.

[2]. Mato A, et al. A first-in-human phase 1 trial of NX-2127, a first-in-class oral BTK degrader with IMiD-like activity, in patients with relapsed and refractory B-cell malignancies. 2022.