Pioneering a new generation of menin inhibitors for acute myeloid leukemia, a disease of high unmet need
Our Approach to Transforming AML Treatment
Acute myeloid leukemia (AML) is a rapidly progressing and aggressive cancer of the blood and bone marrow characterized by the uncontrolled growth of abnormal myeloid cells that fail to mature properly.
Despite advances in targeted therapies, the prognosis for many AML patients remains poor and treatment often fails to address the underlying genetic drivers, resulting in significant toxicity and limited long-term benefit for many patients.
Structurally optimised inhibitors bind precisely within the KMT2A interface on menin.
Menin Inhibition
A key driver of AML is the protein–protein interaction between menin and KMT2A, a gene that encodes the enzyme lysine methyltransferase 2A (also known as MLL, or mixed-lineage leukemia protein). In normal cells KMT2A helps control transcription and differentiation.
However, in certain subtypes of AML, the binding of menin to KMT2A drives the up-regulation of genes which directly contribute to the formation and maintenance of leukemic cells.
CHARM’s molecules are designed to bind precisely within the same binding volume as KMT2A. This means that any mutation that disrupts the binding of CHARM’s molecules would also disrupt the binding of KMT2A, ensuring that leukemogenic signaling is not enabled.
Menin inhibitor blocks interaction between menin and KMT2A. Inhibition of binding of menin to KMT2A enables differentiation and apoptosis of otherwise leukemogenic cells.
Menin inhibitors have emerged in recent years as an important and clinically-validated therapeutic class in the treatment of AML. By disrupting the binding of the KMT2A protein to menin, these inhibitors restore normal gene regulation, triggering differentiation and apoptosis of malignant cells.
A key driver of AML is the protein–protein interaction between menin and KMT2A, a gene that encodes the enzyme lysine methyltransferase 2A (also known as MLL, or mixed-lineage leukemia protein). In normal cells KMT2A helps control transcription and differentiation.
However, in certain subtypes of AML, the binding of menin to KMT2A drives the up-regulation of genes which directly contribute to the formation and maintenance of leukemic cells.
Menin Inhibition Functions in AML by preventing the binding of menin to KMT2A. Binding of menin to KMT2A drives up-regulation of “stemness” genes that cause proliferation phenotype, driving leukemogenesis.
Overcoming resistance by design
CHARM’s Approach_
CHARM Therapeutics is pioneering a new generation of menin inhibitors, designed to overcome the limitations of first-generation therapies and transform outcomes for patients with AML. Resistance mutations in the menin protein can arise early in the treatment paradigm, preventing the binding of menin inhibitors and enabling progression of disease.
CHARM has leveraged its proprietary protein-ligand co-folding platform DragonFold to identify next-generation menin inhibitors that retain activity against all publicly described resistance mutations.
Candidate_
CHARM has identified a development candidate that is potent against all known clinical resistance mutations and has demonstrated robust tumor regression in pre-clinical models.
This molecule is predicted to be efficacious at low human doses without increase of QTc interval, and do not inhibit enzymes responsible for drug-drug interactions. Through the design of high quality molecules, CHARM aims to unlock the full potential of menin inhibition for AML patients and to deliver deeper and more durable treatment responses. Clinical development is expected to start early in 2026.
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