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BACKGROUND
Myeloproliferative neoplasms such as acute myeloid leukemia (AML) are cancers of the bone marrow and blood. Incidence of AML range from 3–8 cases per 100,000 globally, predominantly in United States and Japan. Standard of care therapies include chemotherapy and allogeneic stem cell transplantation to help prolong remission. However, the discovery of novel molecular profiles in AML has now defined several subsets with differing prognosis and a suite of targeted therapeutics. Despite these advances in understanding the genetic heterogeneity of AML and new drug approvals, long-term survival is <50% which is attributed to relapse or treatment resistance. Thus, there is a strong unmet need for new therapeutics to demonstrate long-term disease control, improved safety profiles and to overcome treatment resistance.
The Casitas B-cell lymphoma (CBL) gene encodes the E3 ubiquitin ligase CBL that functions as a negative regulator of tyrosine kinase (TK) signaling, which are commonly targeted in AML. Ubiquitination of TK receptors by CBL promotes degradation and signal termination. The loss of CBL function is implicated in several forms of leukemia.
DESCRIPTION OF THE INVENTION
The McGlade Laboratory at The Hospital for Sick Children interrogated the interaction between Src-like adaptor proteins (SLAP and SLAP2) that are involved in CBL mediated down regulation of TK receptors (e.g., FLT3, c-myc).
Typically, CBL E3 ligase activity is stimulated by phosphorylation of Tyr371 but there is also a phosphorylation independent inhibition via an interaction with the C-terminal domain of SLAP/SLAP2. The mechanism for this was unknown until the McGlade lab solved the X-ray crystal structure of the CBL tyrosine kinase binding domain (TKBD) in complex with SLAP2. Thus, this novel and alternative mechanism of CBL activation in hematopoietic cells can be leveraged for the treatment of myeloid malignancies.
DEVELOPMENT STAGE
Assays were developed to quantify CBL activation and discover molecules that mimic the SLAP2/CBL protein-protein interaction and thereby increase the downstream ubiquitination and subsequent degradation of TK receptors. A peptidomimetic screen was performed to find CBL activating compounds.
Confirmed hits are now being validated in cell-based assays. These compounds could be novel means of treating cancers that result from an inhibition of CBL ubiquitination activity.
COMMERCIAL APPLICATIONS & ADVANTAGES
SLAP/SLAP2 binding does not stimulate CBL ubiquitination activity to the same magnitude as phosphorylation of Tyr371. This suggests that targeting the SLAP/SLAP2 protein interaction site is a more nuanced method for modulating CBL activity while also offering a higher degree of specificity over targeting a phosphorylation site.
Drugs developed in this program would be effective in all cancers where decreased CBL activity is implicated. This includes cancers such as Leukemia (AML, JMML, CMML, CML), lung, head and neck cancer, moyamoya angiopathy and Noonan syndrome.
KEY REFERENCES
- Wybenga-Groot, et al. 2021 “SLAP2 Adaptor Binding Disrupts C-CBL Autoinhibition to Activate Ubiquitin Ligase Function.” Journal of Molecular Biology 433, no. 8: 166880.
- Wybenga-Groot, et al. 2015 “RTK SLAP down: The Emerging Role of Src-like Adaptor Protein as a Key Player in Receptor Tyrosine Kinase Signaling.” Cellular Signalling 27, no. 2: 267–74.
PATENT STATUS
National phase applications are pending in the US covering an agent that is a SLAP/SLAP2 mimetic in the treatment of cancer. Serial Number: 18/000,713.
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