The orally bioavailable GSPT1/2 degrader SJ6986 exhibits in vivo efficacy in acute lymphoblastic leukemia

Abstract

Advancing cure rates for high-risk acute lymphoblastic leukemia (ALL) has been limited by the lack of agents that effectively kill leukemic cells sparing normal hematopoietic tissue. Molecular glues direct the cellular ubiquitin ligase cellular machinery to target neosubstrates for protein degradation. We developed a novel Cereblon modulator, SJ6986 that exhibited potent and selective degradation of GSPT1 and GSPT2, and cytotoxic activity against childhood cancer cell lines. Here we report in vitro and in vivo testing of the activity of this agent in a panel of ALL cell lines and xenografts. SJ6986 exhibited similar cytotoxicity to the previously described GSPT1 degrader CC-90009 in a panel of leukemia cell lines in vitro, resulting in apoptosis and perturbation of cell cycle progression. SJ6986 was more effective than CC-90009 in suppressing leukemic cell growth in vivo, partly attributable to favorable pharmacokinetic properties, and did not significantly impair differentiation of human CD34+ cells ex vivo. Genome wide CRISPR/Cas9 screening of ALL cell lines treated with SJ6986 confirmed components of the CRL4CRBN complex, associated adaptors, regulators and effectors were integral in mediating the action of SJ6986. SJ6986 is a potent, selective, orally bioavailable GSPT1/2 degrader that shows broad antileukemic activity and has potential for clinical development.

Selective CK1α degraders exert antiproliferative activity against a broad range of human cancer cell lines

“…1a lenalidomide and pomalidomide were inactive (blue box), indicating that degradation of classical IMiD neosubstrates is not essential for the viability of these cell lines. CC-885 28 and our previously disclosed GSPT degrader (SJ6986) 27,29 were cytotoxic to all cell lines in the panel (yellow box, Fig. 1a), consistent with the previously observed anti-proliferative effect of degrading this essential protein.…”

Direct-to-biology, automated, nano-scale synthesis, and phenotypic screening-enabled E3 ligase modulator discovery

“…Thus, we discovered the exceedingly potent compound E14. Compared to pomalidomide, E14 shows enhanced proteasome-dependent degradation of IKZF1/3 and GSPT1 as well as its close homolog GSPT2 which has so far only been described as IMiD neo-substrate in two other publications 37,38 . E14 has also broader and enhanced anti-proliferative activity across a large set of cancer cell lines.…”

Genomic determinants of response and resistance to inotuzumab ozogamicin in B-cell ALL

“…Whole genome CRISPR/Cas9 screen was performed as previously described. 44 Briefly, human CRISPR Knockout Pooled Library (Brunello) [45][46][47] (Addgene #73179) lentivirus was obtained from the Center for Advanced Genome Engineering at St. Jude. NALM-6 cells were infected with the genome-wide sgRNA library at 20%-40% transduction efficiency to ensure no more than one sgRNA per cell, and infections were performed in three biological replicates per cell line and achieved a target representation of ~500 cells per sgRNA.…”