生物活性

• 靶点	KDM1A IC50:13nM

• 描述SP2509 is a selective LSD1 antagonist with IC50 value of 13nM. Treatment with SP2509 induced more apoptosis and more cell growth inhibition of AML cells expressing mutant NPM1, OCI-AML3 cells, than mixed-lineage leukemia fusion oncoproteins (MV4-11 and MOLM13 cells) at concentration of 1μM for 48h and 96h, respectively. SP2509 at concentration increased the mRNA levels of p57KIP, KLF4 and p21 in OCI-AML3 cells post 16h. Differentiation of cultured and primary AML cells induced by 1μM SP2509 could also be observed after 96h. Intraperitoneal injection with SP2509 twice per week for 3 weeks significantly improved the survival of immunedepleted mice following tail-vein infusion and engraftment of cultured (OCI-AML3 xenografts, at dose of 25mg/kg) or primary human AML cells (at dose of 15mg/kg). Combined treatment of panobinostat could synergize with SP2509 and significantly improved the survival of the mice engrafted with the human AML cells, without exhibiting any toxicity. Inhibition of LSD1 by SP2509 partially reversed the reduction of H3K4 methylation in Utx-deficient HSPCs (hematopoietic stem and progenitor cells) post 12h and reversed the reduction of the expression of differentiation-related and tumor suppressor genes by Utx loss. Administration of SP2509 promoted the differentiation of Utx-null AML cells both in vitro and in vivo and, therefore, extended the survival of the leukemic mice.
• 作用机制SP2509 attenuated the binding of LSD1 with the corepressor CoREST, increased the permissive H3K4Me3 mark on the target gene promoters.^[1]

• 动物研究
  剂量	Mice: 25 mg/kg[1] (i.p.), 0.5 mg/kg[3] (i.p.)
  给药途径	i.p.