Nx-2127, a Degrader of BTK and IMiD Neosubstrates, for the Treatment of B-Cell Malignancies

Bruton's tyrosine kinase (BTK) plays a key role in cell survival in B cell malignancies, such as chronic lymphocytic leukemia (CLL). Covalent inhibitors of BTK, such as ibrutinib and acalabrutinib, while effective, have been associated with the occurrence of resistance mutations. The most prevalent site of mutation, C481, renders covalent BTK inhibitors unable to form a covalent bond with BTK leading to diminished efficacy and disease progression. Small molecule-induced protein degradation offers a unique approach to target BTK for the treatment of B-cell malignancies. Chimeric Targeting Molecules (CTMs) catalyze ubiquitylation and proteasomal degradation of target proteins and are comprised of a ubiquitin ligase binding element (“harness”), a linker, and a target binding element (“hook”). NX-2127 is a CTM that contains a BTK hook linked to a cereblon (CRBN) harness. NX-2127 degrades 50% of cellular BTK (DC50) at 1 μM for ibrutinib). Oral administration of NX-2127 in mice leads to dose-proportional exposure in plasma and BTK degradation to In addition to potent BTK degradation, NX-2127 possesses IMiD-like properties through the design of the CRBN binding harness that catalyzes the degradation of CRBN neosubstrates Aiolos (IKZF3) and Ikaros (IKZF1). This activity is associated with increased T cell activation and anti-tumor effects of the IMiD drugs lenalidomide and pomalidomide. In primary human T cells, NX-2127 catalyzes the degradation of Aiolos and Ikaros with of 25 nM and 54 nM, respectively, potencies which are similar to those of lenalidomide (20 nM and 343 nM, respectively). Corresponding with such degradation, NX-2127 stimulates T cell activation as measured by increased IL-2 production in primary human T Cells in a manner similar to lenalidomide and pomalidomide. The dual activity of BTK degradation combined with immunomodulation of NX-2127 supports its development for the treatment of B-cell malignancies. Disclosures Robbins: Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Kelly: Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Tan: Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. McIntosh: Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Wu: Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Konst: Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Kato: Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Peng: Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Mihalic: Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Weiss: Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Perez: Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Tung: Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Kolobova: Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Borodovsky: Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Rountree: Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Tenn-McClellan: Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Noviski: Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Ye: Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Basham: Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Ingallinera: Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. McKinnell: Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Karr: Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Powers: Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Guiducci: Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Sands: Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company.