A novel Menin-MLL1 inhibitor, DS-1594a, prevents the progression of acute leukemia with rearranged MLL1 or mutated NPM1

Abstract

Background Mixed lineage leukemia 1-rearranged (MLL1-r) acute leukemia patients respond poorly to currently available treatments and there is a need to develop more effective therapies directly disrupting the Menin‒MLL1 complex. Small-molecule–mediated inhibition of the protein‒protein interaction between Menin and MLL1 fusion proteins is a potential therapeutic strategy for patients with MLL1-r or mutated-nucleophosmin 1 (NPM1c) acute leukemia. In this study, we preclinically evaluated the new compound DS-1594a and its salts. Methods We evaluated the preclinical efficacy of DS-1594a as well as DS-1594a·HCl (the HCl salt of DS-1594a) and DS-1594a·succinate (the succinic acid salt of DS-1594a, DS-1594b) in vitro and in vivo using acute myeloid leukemia (AML)/acute lymphoblastic leukemia (ALL) models. Results Our results showed that MLL1-r or NPM1c human leukemic cell lines were selectively and highly sensitive to DS-1594a·HCl, with 50% growth inhibition values < 30 nM. Compared with cytrabine, the standard chemotherapy drug as AML therapy, both DS-1594a·HCl and DS-1594a·succinate mediated the eradication of potential leukemia-initiating cells by enhancing differentiation and reducing serial colony-forming potential in MLL1-r AML cells in vitro. The results were confirmed by flow cytometry, RNA sequencing, RT‒qPCR and chromatin immunoprecipitation sequencing analyses. DS-1594a·HCl and DS-1594a·succinate exhibited significant antitumor efficacy and survival benefit in MOLM-13 cell and patient-derived xenograft models of MLL1-r or NPM1c acute leukemia in vivo. Conclusion We have generated a novel, potent, orally available small-molecule inhibitor of the Menin-MLL1 interaction, DS-1594a. Our results suggest that DS-1594a has medicinal properties distinct from those of cytarabine and that DS-1594a has the potential to be a new anticancer therapy and support oral dosing regimen for clinical studies (NCT04752163).

The future of HOXA-expressing leukemias: Menin inhibitor response and resistance

“…This leads to differentiation and ultimately apoptosis of leukemic cells [34]. Currently, numerous small molecules disrupting the interaction between KMT2A and Menin (referred to as Menin inhibitors) are in development [37], and being investigated in clinical trials [38–41,42 ▪▪ ,43]. Menin inhibitors have recently shown promising results not only in preclinical models of these genetically defined leukemia subsets, but also in corresponding early phase clinical trials [38–40,42 ▪▪ ,44–46].…”

“…Furthermore, a phase I/II clinical trial is investigating the efficacy of the Menin inhibitor DS-1594 (NCT04752163) in AML and ALL, both as a monotherapy and in combination with the chemotherapy-based regimens azacytidine and venetoclax or mini-HCVD (cyclophosphamide, vincristine and dexamethasone). This small molecule had shown promising results in preclinical studies [39], but the clinical trial results have yet to be published. DSP-5336 is another Menin inhibitor that similarly showed preclinical activity in acute leukemias with KMT2A -rearrangement or NPM1c [40] and a phase I/II clinical trial (NCT04988555) assesses its efficacy in adult AML and ALL patients.…”

Breakthrough treatment choice for Acute Myeloid Leukemia in pediatric and adult patients: Revumenib, an oral selective inhibitor of KMTA2Ar

“…Acute myeloid leukemia (AML) represents the predominant manifestation of acute leukemia in the adult population, whereas in children, it ranks second in terms of frequency. It is characterized by genetic mutations and epigenetic dysregulation resulting in a heterogeneous population of malignant cells with blocked differentiation resulting in increased proliferation and self-renewal activity 1 . Every year 20,000 new cases of AML are diagnosed in the United States, whereas the global burden of the disease is believed to range between 119,000 to 352,000 cases per annum.…”

“…This leads to the expression of chimeric MLL1 fusion proteins (ML-FP) that drive leukemic gene expression and proliferation and prevent hematopoietic differentiation, consequently giving rise to a particularly aggressive subtype of leukemia with an unfavorable outcome. 1,4 Chromosomal rearrangements involving KMT2A gene are prevalent in neonates with acute leukemia, 5 and affects 75% of newborns with ALL. 6 Research findings suggest that this crucial molecular alternation takes place antenatally, leading to leukemia during the infantile period.…”

“…2 Furthermore, existing research has suggested that circRNAs are capable of playing a role in the post-transcriptional regulation of AML by binding miRNAs, activating downstream signaling cascades, and regulating the expression of related genes, closely correlated with a wide variety of processes of AML. 7 AML has a poor prognosis and a considerable tendency to relapse 1 therefore, the need for effective treatment is undeniable.…”