2-Pyrazinecarboxamide, 3-[[4-[1-[[(3S)-1-[2-(2,6-dioxo-3-piperidinyl)-2,3-dihydro-1,3-dioxo-1H-isoindol-5-yl]-3-pyrrolidinyl]methyl]-4-piperidinyl]phenyl]amino]-5-[(3R)-3-(3-methyl-2-oxo-1-imidazolidinyl)-1-piperidinyl]-

NRX-0492 is an orally active PROTAC-class BTK degrader. NRX-0492 catalyzes BTK ubiquitination and proteasome degradation (DC50 ≤ 0.2 nM, DC90 ≤ 0.5 nM)[1]. NRX-0492 inhibits B cell receptor (BCR) mediated signaling, transcription programs, and chemokine secretion. NRX-0492 can bind non-covalently to the BTK binding domain and cereblon, which is an adapter protein in the E3 ubiquitin ligase complex[1]. NRX-0492 consists of a target protein ligand (red part) BTK-IN-40 (HY-170324), an E3 ligase ligand (blue part) Thalidomide 5-fluoride (HY-W087383), and a PROTAC linker (black part) (3R)-3-Pyrrolidinemethanol (HY-60263). E3 ubiquitin ligase and linker can form Thalidomide 5-pyrrolidine-CHO (HY-49372A); the active control for the target protein ligand is BTK ligand 12 (HY-49421).

[1] Zhang D, et al. NRX-0492 degrades wild-type and C481 mutant BTK and demonstrates in vivo activity in CLL patient-derived xenografts. Blood. 2023 Mar 30;141(13):1584-1596. DOI:10.1182/blood.2022016934