BMS-986397, a First-in-Class Molecular Glue Degrader of Casein Kinase 1α (CK1α) for the Treatment of Acute Myeloid Leukemia (AML) and High-Risk Myelodysplastic Syndrome (HR-MDS) Harboring Functional TP53

Introduction: The Casein Kinase 1α (CK1α) gene resides on chromosome 5q and has haploid status in del5q MDS (Myelodysplastic Syndrome). Lenalidomide is a weak, but significant degrader of CK1α, and has clinical efficacy in del5q MDS relative to non-del5q MDS. Therefore, development of a strong degrader of CK1α that may have activity in myeloid malignancies irrespective of 5q status is warranted. We identified BMS-986397 as a potent, specific, oral CELMoD molecular glue degrader of CK1α. Here, we present preclinical evidence of p53-dependent efficacy of BMS-986397 in AML (Acute Myeloid Leukemia) and HR-MDS (High-Risk Myelodysplastic Syndrome).

Methods: To assess the anti-proliferative activity and molecular mechanism of BMS-986397, AML parental and genetically engineered cell lines with CRISPR/Cas9-mediated knockout of Cereblon (CRBN) or TP53 or overexpressing a non-degradable CK1α mutant were evaluated by proliferative assays, flow cytometry, and immunoblotting. As BMS-986397 is pharmacology active in different species, informative in vivo studies in rodent models and in ex vivo models using primary samples from healthy volunteers and AML patients were conducted to assess pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity. Additionally, single- and repeat-dose toxicity studies in rats, monkeys and primary human samples were executed to determine the CK1α on-target toxicity and the toxicologic profile of BMS-986397. All preclinical data described above were leveraged and integrated into a PK/PD model to establish key safety, efficacy, and PD relationships informing the starting dose/schedules for the FIH (Firs-in-Human) clinical study.

Results: BMS-986397 exhibits a strong antiproliferative effect in TP53 WT (Wild-Type) AML cancer cell lines through potent and selective degradation of CK1α regardless of FAB subtype or any common oncogenic-driver mutations, with the exception of TP53. Degradation of CK1α leads to p53 stabilization and the consequent induction of p53 transcriptional targets including p21, PUMA, and BAX, thereby inducing cell cycle arrest and acute apoptosis of AML cells. This anti-AML activity is dependent on upon CRBN, CK1α, and p53. The growth inhibitory effect of BMS-986397 is also observed in hematopoietic progenitors and leukemic cells from multiple AML patient samples harboring functional p53, while sparing normal T-lymphocytes. Normal hematopoietic progenitors are less responsive to BMS-986397 treatment in a time and dose-dependent fashion. Pharmacodynamic (PD) studies indicate that sustained CK1α degradation for a minimum of 48 hours is required to stabilize p53 and, therefore, achieve antileukemic efficacy compromising AML blasts viability. A faster recovery of normal marrow progenitors and stem cells is observed compared to AML blasts, further supporting a reasonable therapeutic index for the treatment of AML and HR-MDS. Similarly, in vivo pharmacology studies in cell line-derived AML xenograft models determined a dose- and schedule-dependent PK/PD relationship, a significant CK1α degradation and consequent activation of downstream pathways led to marked tumor burden reduction and prolonged mice survival. Integrative modeling of PK/PD, efficacy, and toxicity data established key safety, efficacy, and target engagement relationships which suggested that short and intense schedules followed by prolonged off-treatment period instead of more frequent intermittent schedules may maximize cytotoxicity on AML blasts while allowing for extended recovery period of hematopoietic progenitors.

Conclusions: BMS-986397 is a novel CELMoD agent with a first in class mechanism targeting CK1α degradation exhibiting strong anti-leukemic activity as a single agent in models of TP53 WT AML and HR-MDS. These data support the clinical investigation of BMS-986397 in patients with R/R AML and HR-MDS patients (NCT04951778).