Conference Day Two
8:00 am Coffee & Networking
8:55 am Chairman’s Opening Remarks
Targeting the Major Kinase Signalling Pathway
9:00 am Targeting RAF Kinases to Overcome Adaptive Resistance to RAS Targeted Therapies
Synopsis
- Clinical and pre-clinical data emphasizes the frequency of on-target and onpathway (ERK-MAPK) adaptive and acquired resistance mechanisms to KRASG12C targeted therapies.
- CRISPR LoF screens in KRAS-G12C inhibitor resistant cell lines reveal gene subsets whose depletion restores sensitivity to KRASG12C inhibitor treatment. RAF kinases, notably CRAF, was uncovered as one such gene.
- CRISPR genetic ablation and acute protein destruction methods, including DTAG, provide unique insights into the kinetics of ERK-MAPK pathway modulation by CRAF. These technologies reveal mechanism of action hypotheses and biomarker opportunities for this challenging onco-target.
9:30 am [VIRTUAL] Sourcing the Immune System to Induce Immunogenic Cell Death In Kras-Colorectal Cancer Cells
Synopsis
- Review how current approaches aimed at inducing immunogenic cell death (ICD) to incite an immune response against cancer neoantigens are based on the use of chemotherapeutics and other agents
- Results are hampered by issues of efficacy, combinatorial approaches, dosing and toxicity. Here, we adopted a strategy based on the use of an immunomolecule that overcomes pharmachemical limitations.
- Cytofluorometry, electron microscopy, RT-PCR, western blotting, apotome immunofluorescence, MLR and xenografts
10:10 am Kinetic Profiling of Reversible & Irreversible Kinase Inhibitors : At Scale & Speed
Synopsis
- Why kinetic profiling matters in drug discovery
- Enzymlogic’s KINETICfinder® and COVALfinder® platforms: optimized for reversible and irreversible inhibitor kinetic profiling in early discovery Case studies that illustrate:
- How kinetic profiling reinforces drug discovery decision making
- Kinetic Selectivity is a superior predictor of efficacy compared to Affinity Selectivity
- How Enzymlogic supports your kinetic investigation
10:25 am Targeting Pantothenate Kinase as an Effective Strategy for Antifungal Drug Development
Synopsis
- Pantothenate kinase (PanK) activity is the first step in Co-enzyme A (CoA) biosynthesis. In fungi, a single PanK gene, CAB1, encodes this function
- A high-throughput chemical screen identified fungal PanK inhibitors and the CAB1 3D structure revealed essential residues for catalysis, inhibitor binding, and future SAR studies
- The fungal PanK were validated as targets for antifungal drug development
10:55 am Morning Networking Break
11:30 am Targeting Oncogenic KRAS-G12D Mutation Employing Engineered Exosomes in Pancreatic Cancer
Synopsis
- Direct inhibitors do not exist for KRAS-G12D
- We engineered exosomes to deliver siRNA specific to Kras-G12D (iExosomes). The iExosomes target pancreatic cancer cells to suppress tumor growth and increase the overall survival of mice with PDAC
- Preclinical studies, GLP-toxicology studies, clinical grade GMP production and FDA IND filing led to a Phase I clinical trial in PDAC
12:00 pm Structural Insights into Emerging Inhibitors Targeting EGFR Mutations
Synopsis
- The structure of lazertinib allows for enhanced potency and mutant selectivity against EGFR T790M
- Next generation mutant EGFR C797S inhibitors bind the kinase domain through H-bonding with conserved catalytic residues
- Spanning ATP-allosteric EGFR inhibitors can be developed exhibiting unique kinase domain binding and mutant selectivity
12:30 pm Tumor-Selective Targeting of Kinase Conformations For Cancer Therapy
Synopsis
- Therapeutic effectiveness of targeted cancer therapies is limited by Incomplete inhibition of the target pathway in the tumor caused by various adaptive resistance mechanisms
- Increased drug dosing or vertical drug combinations to overcome resistance are limited by on-target toxicities in normal tissue and low Therapeutic Index
- Improved therapies require drugs and drug combinations that target tumor-selective kinase conformations to achieve both potent antitumor efficacy and a high Therapeutic Index
1:00 pm Lunch & Networking
Improving Response Rates Through Well-Tested, Powerful Combination Therapies
2:00 pm Lymphatropic Combination Therapy
Synopsis
- Targeting MAPK and PI3K/mTOR pathways is critical due to crosstalk
- Combination therapy strategies have been hampered by dose-limiting toxicities
- A Lymphatropic single agent orally bioavailable mutikinase inhibitor provides a path forward
2:30 pm [VIRTUAL] Targeting Focal Adhesion Kinase (FAK) for the treatment of cancer and fibrotic diseases
Synopsis
- Amplia’s opportunity with AMP945 a FAK inhibitor for combination therapies
- Preclinical data demonstrating FAK’s role modulating the tumour and in the tumour environment
- Clinical evidence gathered so-far that supports progression of AMP945 combination therapy in patients with advanced pancreatic cancer
Targeting Established Pharmacological Mechanisms in Alternative Indications Beyond Oncology to Meet Unmet Needs
3:00 pm Novel Potential Applications of Kinase Activators And Inhibitors In Neurological Conditions
Synopsis
- The interplay between potassium channels and protein kinases appears to play important roles in physiology and disease
- otassium channels can lead to activation and/or inhibition of kinases
- The talk will explore potassium channels-kinases interactions in mouse models of dementia and developmental and epileptic encephalopathies