Pioneering a new generation best-in-class menin inhibitor 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 with a 28% five-year survival rate. Current first line treatments fail to address the underlying genetic drivers of the disease, 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 many instances 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 a disease state, the binding of menin to KMT2A drives the upregulation of genes which directly contribute to the formation and maintenance of leukemic 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.
CHARM’s next generation menin inhibitor is designed to bind precisely within the same binding volume as KMT2A. This means that any mutation that disrupts the binding of CHARM’s molecule 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 (cell death) of otherwise leukemogenic (cancerous) cells.
Resistance mutations in menin are linked to loss of response
Whilst first generation menin inhibitors represent a major breakthrough in treatment of AML, the observation of resistance mutations in the menin protein has been linked to loss of potency of these molecules and is considered likely to compromise the durability of response and patient outcomes.
Addressing resistance by design
CHARM’s menin inhibitor is designed to address resistance by closely mimicking the binding of KMT2A to menin. As a result, CHARM’s molecule is potent against all publicly described resistance mutations and has demonstrated robust tumor regression in pre-clinical models.
CHARM’s next generation menin inhibitor is predicted to be efficacious at low human doses without increase of QTc interval. CHARM aims to unlock the full potential of menin inhibition for AML patients and to deliver deeper and more durable treatment responses.
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.
