SJ988497

SJ988497 is a PROTAC JAK2 degrader. SJ988497 potently inhibits CRLF2-rearranged (CRLF2r) cell proliferation and degrades the CRBN neosubstrate GSPT1. SJ988497 consists of a Ruxolitinib (HY-50856) derivative, linker, and CRBN ligand Pomalidomide. SJ988497 can be used in the research of acute lymphoblastic leukemia (ALL)[1].

Research Areas >> Cancer

Signaling Pathways >> JAK/STAT Signaling >> JAK

Signaling Pathways >> Epigenetics >> JAK

Signaling Pathways >> Stem Cell/Wnt >> JAK

Signaling Pathways >> PROTAC >> PROTAC

JAK2

SJ988497 (compound 7) 在 Caco-2 测定实验中增加细胞渗透性，表观渗透系数 (Papp) 为 19.12 nm/s[1]。 SJ988497 抑制 parental MHH-CALL-4 细胞活力，EC50 为 0.4 nM，抑制 MHH-CALL-4 细胞的 EC50 为 3456.2 nM，这种抑制作用可以被 30 μM Lenalidomide (HY-A0003) 阻断[1]. SJ988497 (1 h, 1 μM) 在 MHH-CALL-4 细胞中产生 JAK 抑制作用[1]。 Cell Viability Assay[1] Cell Line: NAL M6, MHH-CALL-2, 697, KOPN49, KOPN75, MHH-CALL-4 cells Concentration: 0.01 nM-100 nM Incubation Time: 72 h Result: Dose-dependently inhibited cell viability in ALL cell lines. Western Blot Analysis[1] Cell Line: MHH-CALL-4 cells Concentration: 1 nM, 10 nM, 100 nM, 1 μM, 4 μM. Incubation Time: 1 h Result: Degraded multiple JAKs (JAK1>JAK3>JAK2>TYK2), and was abolished by knockdown of CRBN.

SJ988497 (compound 7) (30 mg/kg，腹腔注射) 可减小脾脏大小和肿瘤负荷，并且耐受性良好，不会减轻体重或扰乱血细胞计数[1]。 SJ988497 (10-100 mg/kg, 腹腔注射, 每天两次) 显示出持续的体内暴露，24 小时后血浆浓度高于细胞实验中 50% 有效浓度值[1]. Animal Model: NSG mice inoculated by CL20SF2-Luc2aYFP cell (i.v.)[1] Dosage: 30 mg/kg Administration: Intraperitoneal injection (i.p.) Result: Reduced leukemia burden in bone marrow, blood, and spleen, as well as total body bioluminescent imaging.

[1]. Chang Y, et al. Degradation of Janus kinases in CRLF2-rearranged acute lymphoblastic leukemia. Blood. 2021 Dec 9;138(23):2313-2326.