KAT2A PROTACs targetting the differentiation of blasts and leukemic stem cells for the treatment of Acute Myeloid Leukaemia
Lead Research Organisation:
CARDIFF UNIVERSITY
Department Name: School of Biosciences
Abstract
Acute Myeloid Leukaemia (AML) is a form of cancer that starts in the bone marrow and moves into the blood. The loss of blood cells to fight infection and to mediate blood clotting frequently leads to sepsis or significant hemorrhage. This cancer is most common in the older population (over 65 years) and is difficult to treat. Current therapies are relatively crude chemotherapeutic "sledgehammers" and are not widely effective and/or are poorly tolerated, particularly by the elderly. This leads to over 70% of patients over 65 years old dying within the first year of diagnosis and fewer than 15% living beyond year 5.
The Medicines Discovery Institute at Cardiff University has developed a novel therapeutic agent which can revolutionise treatment of this disease and treat all AML patients, with the potential to be well tolerated in the vulnerable elderly population. We will do this by targeting a specific protein in the body, known as KAT2A, which plays a key role in blocking the body from recognising and destroying the cancer cells.
Our approach has exploited a novel technology that allows us to harness the body's own molecular waste disposal systems within the cell to remove this target protein. This solution was unimaginable 5 years ago, but now presents us with the opportunity to advance a technology solution that could be widely used and would be less toxic than current treatments.
Our project has many years of discovery effort behind it, and has completed an extensive campaign of optimisation and characterisation to identify three advanced molecules which have the potential to progress into clinical trials. Now, we need to further study these molecules to complete the data package that is required by regulatory agencies and to select the best of these molecules as the potential new therapy. These studies will establish the best dose to use for our novel molecules and inform us on how best to use these molecules to help patients.
These experiments significantly enhance the potential for onward investment by groups focused on the development of new cancer treatments for this patient population.
The Medicines Discovery Institute at Cardiff University has developed a novel therapeutic agent which can revolutionise treatment of this disease and treat all AML patients, with the potential to be well tolerated in the vulnerable elderly population. We will do this by targeting a specific protein in the body, known as KAT2A, which plays a key role in blocking the body from recognising and destroying the cancer cells.
Our approach has exploited a novel technology that allows us to harness the body's own molecular waste disposal systems within the cell to remove this target protein. This solution was unimaginable 5 years ago, but now presents us with the opportunity to advance a technology solution that could be widely used and would be less toxic than current treatments.
Our project has many years of discovery effort behind it, and has completed an extensive campaign of optimisation and characterisation to identify three advanced molecules which have the potential to progress into clinical trials. Now, we need to further study these molecules to complete the data package that is required by regulatory agencies and to select the best of these molecules as the potential new therapy. These studies will establish the best dose to use for our novel molecules and inform us on how best to use these molecules to help patients.
These experiments significantly enhance the potential for onward investment by groups focused on the development of new cancer treatments for this patient population.
Technical Summary
Acute Myeloid Leukaemia (AML) is a blood and bone marrow cancer which primarily affects the over-65 age group and if untreated is invariably fatal. However, the current chemotherapeutic drugs are poorly tolerated in the elderly, and as a consequence there is a 5-year survival rate of only 5%. There is therefore a high unmet need to identify novel approaches to the treatment of AML.
AML is defined by the proliferation of undifferentiated myeloid progenitor cells (blasts), which accumulate and lead to toxic pathology, ultimately causing death. Recent studies have described the role of Lysine acetyltransferase A (KAT2A) in regulating the transcription complexes that are critical in maintaining cells in an undifferentiated state. The depletion of KAT2A results in the terminal differentiation of blasts with the potential to address the underlying cause of AML and revolutionise patient therapy.
Unfortunately, KAT2A is not druggable by traditional small molecules so our approach uses a highly novel PROTAC (proteolysis-targeting chimaera) approach to degrade KAT2A protein. Our prototype PROTAC was able to not only induce the terminal differentiation of cancer cell lines and patient blasts but also demonstrated an in vivo Proof-of-Concept (PoC) following oral dosing. A major lead optimisation project delivered three pre-candidates with superior in vitro and in vivo profiles. The primary goal of this project is to further characterise these three pre-candidates in order to select a clinical candidate. The programme will be divided into the following work packages (WPs) to position the selected lead PROTAC for onward investment into Phase I/II.
WP 1a - select the development candidate from three pre-candidates based on PK/PD, tolerability and developability.
WP 1b - determine preliminary therapeutic index in efficacy/tox models.
WP 2 - generate a value-adding data package to support onward progression.
WP 3 -Translational Biomarker work to enable clinical studies.
AML is defined by the proliferation of undifferentiated myeloid progenitor cells (blasts), which accumulate and lead to toxic pathology, ultimately causing death. Recent studies have described the role of Lysine acetyltransferase A (KAT2A) in regulating the transcription complexes that are critical in maintaining cells in an undifferentiated state. The depletion of KAT2A results in the terminal differentiation of blasts with the potential to address the underlying cause of AML and revolutionise patient therapy.
Unfortunately, KAT2A is not druggable by traditional small molecules so our approach uses a highly novel PROTAC (proteolysis-targeting chimaera) approach to degrade KAT2A protein. Our prototype PROTAC was able to not only induce the terminal differentiation of cancer cell lines and patient blasts but also demonstrated an in vivo Proof-of-Concept (PoC) following oral dosing. A major lead optimisation project delivered three pre-candidates with superior in vitro and in vivo profiles. The primary goal of this project is to further characterise these three pre-candidates in order to select a clinical candidate. The programme will be divided into the following work packages (WPs) to position the selected lead PROTAC for onward investment into Phase I/II.
WP 1a - select the development candidate from three pre-candidates based on PK/PD, tolerability and developability.
WP 1b - determine preliminary therapeutic index in efficacy/tox models.
WP 2 - generate a value-adding data package to support onward progression.
WP 3 -Translational Biomarker work to enable clinical studies.
