Our pipeline opportunities include selective inhibitors within signal networks of SYK, FLT3, and LRRK2. Our programs target a selective SYK inhibitor for rheumatoid arthritis, a selective FLT3 inhibitor for acute myeloid leukemia, as well as a LRRK2 selective inhibitor for the
treatment of Parkinson’s disease.
Details of each project
1. SYK: Spleen Tyrosine Kinase (SYK) is an intracellular, non-receptor cytoplasmic protein tyrosine kinase. It serves as a key mediator of Fc and B cell receptors that produce signals in inflammatory cells including macrophages, neutrophiles, master cells, NK cells and B cells. Immunoreceptors, such as Fc and B cell receptors, are important for both allergic and antibody-mediated immune diseases; therefore, interfering with SYK positioned upstream within the signaling pathway may be viable as an effective therapeutic target. A SYK inhibitor is likely to weaken both the initiation of the disease and its effector phase, by blocking B-cell receptor signaling and FcgR signaling through neutrophils present in the synovial membrane respectively. In addition, SYK inhibition has an additional benefit of preventing osteoclast maturation, attenuating bone erosion, joint destruction and osteopoenia associated with rheumatoid arthritis (RA). RA is often progressive and debilitating, affecting nearly 2.1 million people in the United States. The current treatment options for RA have potentially significant shortcomings and/or side effects. Presently, RA patients receive multiple drugs depending on the extent and aggressiveness of the disease. Most RA patients require some form of disease modifying anti-rheumatic drugs including methotrexate or biologic TNF-a blocking agents such as Enbrel. Up to 30 percent of patients continue to be resistant to these approaches. Moreover, a range of toxicities occurs, including gastrointestinal complications, kidney damage, opportunistic infections and increased incidence of lymphoma. Therefore, RA requires a safer and more effective therapeutic strategy. In this aspect, SYK offers a target-based approach that will provide multiple solutions for unmet needs. A small molecule SYK inhibitor is orally available with a better physicochemical profile and could serve as a better therapeutic alternative by reducing the cost of drug and avoiding painful delivery methods.
1. SYK: Spleen Tyrosine Kinase (SYK) is an intracellular, non-receptor cytoplasmic protein tyrosine kinase. It serves as a key mediator of Fc and B cell receptors that produce signals in inflammatory cells including macrophages, neutrophiles, master cells, NK cells and B cells. Immunoreceptors, such as Fc and B cell receptors, are important for both allergic and antibody-mediated immune diseases; therefore, interfering with SYK positioned upstream within the signaling pathway may be viable as an effective therapeutic target. A SYK inhibitor is likely to weaken both the initiation of the disease and its effector phase, by blocking B-cell receptor signaling and FcgR signaling through neutrophils present in the synovial membrane respectively. In addition, SYK inhibition has an additional benefit of preventing osteoclast maturation, attenuating bone erosion, joint destruction and osteopoenia associated with rheumatoid arthritis (RA). RA is often progressive and debilitating, affecting nearly 2.1 million people in the United States. The current treatment options for RA have potentially significant shortcomings and/or side effects. Presently, RA patients receive multiple drugs depending on the extent and aggressiveness of the disease. Most RA patients require some form of disease modifying anti-rheumatic drugs including methotrexate or biologic TNF-a blocking agents such as Enbrel. Up to 30 percent of patients continue to be resistant to these approaches. Moreover, a range of toxicities occurs, including gastrointestinal complications, kidney damage, opportunistic infections and increased incidence of lymphoma. Therefore, RA requires a safer and more effective therapeutic strategy. In this aspect, SYK offers a target-based approach that will provide multiple solutions for unmet needs. A small molecule SYK inhibitor is orally available with a better physicochemical profile and could serve as a better therapeutic alternative by reducing the cost of drug and avoiding painful delivery methods.
One of our orally available drug candidate leads showed not only selective and highly potent activity (single nM range) but also a good safety in hERG and CYP inhibition. Furthermore, it showed great efficacy in collagen induced arthritis (CIA) mouse models, manifested by
in vivo imaging analysis. Thus, we expect these leads to proceed to the preclinical stage of drug development at Q4, 2011.
A Novel SYK Selective Inhibitor for the Treatment of Rheumatoid Arthritis
ABSTRACT
2. FLT3: Mutations within the FMS-like tyrosine kinase 3 (FLT3), a class III receptor tyrosine kinase (RTK) family gene on chromosome 13q12, have been detected in up to 35% of acute myeloid leukemia (AML) patients. FLT3 mutations represent one of the most frequently identified genetic alterations in AML. Two major classes of activating FLT3 mutations have been identified in AML patients: intra-tandem-duplications (ITD) and tyrosine kinase domain (TKD) point mutations. ITD-mutations cause constitutive activation of FLT3, leading to aberrant activation of multiple downstream pathways such as PI3K/AKT, MAPK/ERK and STAT5. In addition, about 5-10% of AML patients display point mutations within the second TKD. In most cases, these mutations result in the substitution of tyrosine for aspartic acid at codon 835 (D835Y). Similar to FLT3-ITDs, TKD-mutations cause constitutive activation of the FLT3 receptor, causing aberrant activation of downstream signaling pathways and factor-independent growth. In these respects, FLT3 has emerged as a promising molecular target in the therapy of AML.
A Novel SYK Selective Inhibitor for the Treatment of Rheumatoid Arthritis
ABSTRACT
2. FLT3: Mutations within the FMS-like tyrosine kinase 3 (FLT3), a class III receptor tyrosine kinase (RTK) family gene on chromosome 13q12, have been detected in up to 35% of acute myeloid leukemia (AML) patients. FLT3 mutations represent one of the most frequently identified genetic alterations in AML. Two major classes of activating FLT3 mutations have been identified in AML patients: intra-tandem-duplications (ITD) and tyrosine kinase domain (TKD) point mutations. ITD-mutations cause constitutive activation of FLT3, leading to aberrant activation of multiple downstream pathways such as PI3K/AKT, MAPK/ERK and STAT5. In addition, about 5-10% of AML patients display point mutations within the second TKD. In most cases, these mutations result in the substitution of tyrosine for aspartic acid at codon 835 (D835Y). Similar to FLT3-ITDs, TKD-mutations cause constitutive activation of the FLT3 receptor, causing aberrant activation of downstream signaling pathways and factor-independent growth. In these respects, FLT3 has emerged as a promising molecular target in the therapy of AML.
One of our FLT3 inhibitor candidate leads not only showed highly potent and selective activity (single nM range) against ITD, D835Y and
other clinical known mutants but also performed better in biochemical analysis and in BaF3 model cells compared to existing competitors’
drugs. Compound washing experiments suggested that our candidate established stronger bonds with the target while remaining reversible.
Moreover, kinase assays revealed that our candidate was more resistant to greater ATP concentration manipulations. Such long lasting
efficacy may lead strong induction of apoptosis of AML cancer cells (see below). These candidate leads will proceed to preclinical stage of
drug development at Q4, 2011.
G-749, a novel selective inhibitor of FLT3 kinase as a therapeutics for AML
ABSTRACT
3. LRRK2: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause late-onset autosomal dominant familial Parkinson’s disease (PD) and also contribute to idiopathic PD. Currently, the following disease-segregating mutations have been identified in LRRK2-linked families including, R1441C/G/H, Y1699C, G2019S and I2020T variants. Of these, G2019S is the most common variant that uniquely contributes to both familial and sporadic PD. LRRK2-linked PD is characterized by the degeneration of substantia nigra dopaminergic neurons. LRRK2 induced degeneration of neurons in vivo is kinase dependent and LRRK2 kinase inhibition provides potentially new neuroprotective paradigm for the treatment of Parkinson’s disease.
G-749, a novel selective inhibitor of FLT3 kinase as a therapeutics for AML
ABSTRACT
3. LRRK2: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause late-onset autosomal dominant familial Parkinson’s disease (PD) and also contribute to idiopathic PD. Currently, the following disease-segregating mutations have been identified in LRRK2-linked families including, R1441C/G/H, Y1699C, G2019S and I2020T variants. Of these, G2019S is the most common variant that uniquely contributes to both familial and sporadic PD. LRRK2-linked PD is characterized by the degeneration of substantia nigra dopaminergic neurons. LRRK2 induced degeneration of neurons in vivo is kinase dependent and LRRK2 kinase inhibition provides potentially new neuroprotective paradigm for the treatment of Parkinson’s disease.
One of our LRRK2 candidate leads showed potent and selective activity against G2019S mutants. Furthermore, it has demonstrated to rescue
dying neuronal cells expressing LRRK2 G2019S mutation back to resembling normal morphology (see below). We plan to test our leads with
our proprietary LRRK2 G2019S mouse model.
