Menin-MLL protein-protein interaction inhibitors: a patent review (2014–2021)

Bai, Huanrong; Zhang, San‐Qi; Lei, Hao; Wang, Fang; Ma, Mengyan; Xin, Minhang

doi:10.1080/13543776.2022.2045947

Cited by 18 publications

(10 citation statements)

References 38 publications

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“…New treatment strategies are urgently needed for both KMT2A/MLL-R + AML and KMT2A/MLL-R + ALL. Therefore, a large panel of drugs are being evaluated as potential therapeutic agents against KMT2A/MLL-R + AML and ALL, including inhibitors of Menin-MLL1 interaction [25][26][27][28] . The present study demonstrates that PTK inhibitors (PTKi), especially inhibitors of FLT3, may have clinical impact potential as therapeutic agents against KMT2A/MLL-R + B-ALL as well as AML.…”

Section: Discussionmentioning

confidence: 99%

Tyrosine kinases in KMT2A/MLL-rearranged acute leukemias as potential therapeutic targets to overcome cancer drug resistance

Uçkun¹,

Qazi²

2022

Cancer Drug Resist

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Aim: The main goal of this study was to elucidate at the transcript level the tyrosine kinase expression profiles of primary leukemia cells from mixed lineage leukemia 1 gene rearranged (KMT2A/MLL-R+) acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) patients. Methods: We evaluated protein tyrosine kinase (PTK) gene expression profiles of primary leukemic cells in KMT2A/MLL-R+ AML and ALL patients using publicly available archived datasets. Results: Our studies provided unprecedented evidence that the genetic signatures of KMT2A/MLL-R+ AML and ALL cells are characterized by transcript-level overexpression of specific PTK. In infants, children and adults with KMT2A/MLL-R+ ALL, as well as pediatric patients with KMT2A/MLL-R+ AML, the gene expression levels for FLT3, BTK, SYK, JAK2/JAK3, as well as several SRC family PTK were differentially amplified. In adults with KMT2A/MLL-R+ AML, the gene expression levels for SYK, JAK family kinase TYK2, and the SRC family kinases FGR and HCK were differentially amplified. Conclusion: These results provide new insights regarding the clinical potential of small molecule inhibitors of these PTK, many of which are already FDA/EMA-approved for other indications, as components of innovative multi-modality treatment platforms against KMT2A/MLL-R+ acute leukemias.

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Section: Discussionmentioning

confidence: 99%

Tyrosine kinases in KMT2A/MLL-rearranged acute leukemias as potential therapeutic targets to overcome cancer drug resistance

Uçkun¹,

Qazi²

2022

Cancer Drug Resist

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“…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- 1). Ziftomenib (KO-539) is a Menin inhibitor also being assessed in patients with R/R adult leukemia.…”

Section: Menin Inhibitor Mechanism Of Actionmentioning

confidence: 99%

“…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].…”

Section: Menin Inhibitor Mechanism Of Actionmentioning

confidence: 99%

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

Wenge,

Armstrong

2023

Current Opinion in Hematology

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Purpose of review We provide an update on the successes and ongoing challenges of Menin inhibition as a novel approach for the treatment of patients with acute leukemias that express HOXA cluster genes including leukemias with KMT2A-rearrangements, NPM1 mutations or NUP98-rearrangements. Initial clinical trials show promising response rates in heavily pretreated patients suggesting these inhibitors may have a significant impact on patient outcome. Furthermore, the development of resistance mutations that decrease drug binding affinity, validates Menin as a therapeutic target in human cancers. Therapeutic strategies aiming at overcoming and preventing resistance, are of high clinical relevance. Recent findings Several Menin inhibitor chemotypes have entered clinical trials. Acquired point mutations have recently been described as a mechanism of resistance towards Menin inhibitors. However, resistance can develop in absence of these mutations. Combination therapies are currently being investigated in preclinical models and in early phase clinical trials. Summary Given the remarkable overall response rates, shedding light on treatment options for patients whose leukemias develop resistance to Menin inhibitors is an imminent clinical need. Studying the underlying mechanisms to inform clinical decision making, and to potentially prevent the development of resistance is of outmost importance.

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“…18−33 Five drugs (SNDX-5613, KO-539, DS-1594, BMF-219, and JNJ-75276617) were advanced into clinical development, which were aimed at the treatment of adult and pediatric patients with relapsed or refractory MLL-r and NPM1 mutations. 34 Despite these major progresses, the development of menin− MLL interaction inhibitors for treating MLL-r leukemia is still in the early stage. The structure types of these drugs are relatively single, and among them, KO-539 was reported to be associated with a grade 5 serious adverse event (patient death) that may be related to differentiation syndrome (DS), which was partially suspended at its phase Ib clinical trial.…”

Section: ■ Introductionmentioning

confidence: 99%

“…The n -propyl group of 1 fitted into the F9 pocket, while the dimethylthiazoline group was localized in the P13 pocket (Figure ). Subsequently, a number of potent small-molecule menin–MLL interaction inhibitors (Figure ) have been reported. − Five drugs (SNDX-5613, KO-539, DS-1594, BMF-219, and JNJ-75276617) were advanced into clinical development, which were aimed at the treatment of adult and pediatric patients with relapsed or refractory MLL-r and NPM1 mutations …”

Section: Introductionmentioning

confidence: 99%

Discovery of Novel, Potent, and Selective Small-Molecule Menin–Mixed Lineage Leukemia Interaction Inhibitors through Attempting Introduction of Hydrophilic Groups

et al. 2022

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Introduction of the N,N-dimethylaminoethoxy group to pyrido[3,2-d]pyrimidine led to the discovery of menin–mixed lineage leukemia (MLL) interaction inhibitor C20. C20 showed strong binding affinity to menin protein and achieved sub-micromolar potency in cell growth inhibition. C20 had good selectivity for the inhibition of the interaction between menin and MLL in the kinase profile evaluation. Pharmacokinetic studies demonstrated that C20 possessed good stability and low clearance rate in liver microsomes and acceptable bioavailability in rats. Subsequent oral administration of C20 showed potent antitumor activity in the MV4;11 subcutaneous xenograft models of MLL-rearranged leukemia. The docking study showed that C20 bound highly with menin, and the N,N-dimethylaminoethoxy group occupied the F9 pocket of menin. This study proved that introducing a hydrophilic group into the F9 pocket of menin would be a new strategy for the design of menin–MLL interaction inhibitors with potent binding affinity and improved physical properties.

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Menin-MLL protein-protein interaction inhibitors: a patent review (2014–2021)

Cited by 18 publications

References 38 publications

Tyrosine kinases in KMT2A/MLL-rearranged acute leukemias as potential therapeutic targets to overcome cancer drug resistance

Tyrosine kinases in KMT2A/MLL-rearranged acute leukemias as potential therapeutic targets to overcome cancer drug resistance

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

Discovery of Novel, Potent, and Selective Small-Molecule Menin–Mixed Lineage Leukemia Interaction Inhibitors through Attempting Introduction of Hydrophilic Groups

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