Cambridge Healthtech Institute 第10回
Kinase Inhibitor Chemistry
( キナーゼ阻害剤の化学 )
Day 1 | Day 2
Tuesday, April 9
7:00 am Registration Open and Morning Coffee
8:00 Welcome Remarks
Nandini Kashyap, Conference Director, Cambridge Healthtech Institute
8:05 Chairperson’s Opening Remarks
8:10 Development of Selective CDK Inhibitors and Degraders
Cyclin-dependent kinases (CDKs) regulate key pathways that are frequently misregulated in cancer, making them attractive drug targets. However, the high sequence and structural conservation shared by CDK family members make the development of CDK-specific pharmacological agents difficult. We have employed several orthogonal strategies to permit the selective inhibition of distinct CDK family members and interrogation of their biological function in normal and disease states.
8:40 FEATURED PRESENTATION: Targeted Degradation of Bruton’s Tyrosine Kinase (BTK)
Proteolysis targeting chimeras present an exciting opportunity to modulate proteins in a manner that is independent of enzymatic or signaling activity. Despite this interest, fundamental questions remain regarding the parameters most critical for achieving potency and selectivity. We have employed a series of biochemical and cellular techniques to investigate
9:10 Structure-Based Predictions of CYP Selectivity, Reactivity, and Regioselectivity
Alain Ajamian, Director, Business Development, Chemical Computing Group
Cytochrome P450 oxidases (CYPs) are heme-containing enzymes responsible for clearing drug molecules through oxidative metabolism. Understanding the interactions between drug molecules and CYPs is critical for evaluating drug efficacy, clearance, toxicity, and drug-drug interactions. Although dozens of crystal structures of the five predominant CYP isoforms have been solved, most of the modeling tools that predict drug-CYP interactions completely neglect this structural information. In this work, both 2D methods and 3D methods are used to predict the isoform selectivity, small molecule reactivity, and regioselectivity of CYPs.
9:40 Networking Coffee Break
10:05 Large Scale Proteomics Approaches to Accelerate Degrader Development for Kinases and Other Challenging Targets in Cancer
Eric S. Fischer,
This presentation will discuss the use of large scale chemical-proteomics approaches to accelerate the development of small molecule degraders as chemical probes and lead candidates. Small molecules capable of inducing protein degradation through recruitment of ubiquitin E3 ligases to target proteins, often referred to as degraders or PROTACs, are a new and promising drug modality. We will discuss general approaches to significantly accelerate the development of novel chemical probes for kinases and other targets in cancer.
10:35 Artificial Intelligence in Kinase Inhibitor Discovery
Istvan J. Enyedy,
Machine learning in combination with automated inhibitor optimization and statistical analysis may be used to accelerate kinase inhibitor discovery. The performance of a prototype artificial intelligence protocol will be presented.
11:05 Defining the Protein Kinase Conformational Space with Machine Learning
We have developed a machine-learning algorithm to classify kinase conformations based on structural features of the kinase domain. Our classification scheme captures known kinase conformations and defines an additional conformational state. Next, we present KinaMetrix, a comprehensive publicly accessible web-resource for studying kinase pharmacology and drug discovery. KinaMetrix enables researchers to investigate and visualize the kinase conformational space as well as small molecule substructures that exhibit conformational specificity.
12:20 pm Session Break
1:15 Chairperson’s Remarks
1:20 Reversing the Paradigm: Protein Kinase C as a Tumor Suppressor
Tim Baffi, Graduate Student, Alexandra Newton's Lab, Department of Pharmacology, University of California San Diego
Protein kinase C (PKC) has historically been considered an oncoprotein. However, our analysis of >100 somatic mutations identified in human cancers reveals that most mutations are loss-of-function and none are activating; in contrast, germline mutations that enhance activity are associated with degenerative diseases. Our results reveal that therapeutic strategies should focus on restoring, rather than inhibiting, PKC activity in cancer.
1:50 Discovery of Soft panJAK Inhibitors for Topical Treatment of Inflammatory Skin Diseases
Daniel R. Greve,
The presentation covers our efforts aiming for selective, pan-JAK inhibitor molecules having a pharmacokinetic profile that allows for high local exposure combined with low systemic exposure, driven by high hepatic clearance. The lead compounds are efficacious in our mouse xenograft model of plaque
2:20 Targeting the Nuclear Translocation of MAPKs as a Novel Anti-Inflammatory and Anti-Cancer Therapy
We have identified two
2:50 Non-Kinase Targets of Protein Kinase Inhibitors
Non-kinase targets of kinase inhibitors can contribute to desired activity, side effects or act as silent bystanders. As the correct understanding of drug’s mechanism of action is critical for the interpretation and success of preclinical as well as clinical drug development, these discoveries highlight the importance of expanding the pharmacology of kinase inhibitors beyond the kinome. I will present kinase inhibitors for which other than kinase targets have been identified and discuss molecular pharmacology guidelines when using kinase inhibitors.
3:20 Sponsored Presentation (Opportunity Available)
3:35 Refreshment Break in the Exhibit Hall with Poster Viewing
4:30 Welcome Remarks from Lead Conference Director
5:05 Plenary Keynote Introduction (Sponsorship Opportunity Available)
5:10 Plenary Keynote: Chemical Biology of Proteostasis
We have recently discovered several macrocyclic compounds that potently and selectively modulate protein homeostasis. I will discuss our recent efforts to unravel their molecular mechanisms.
6:00 Welcome Reception in the Exhibit Hall with Poster Viewing
7:00 Close of Day
Day 1 | Day 2
Wednesday, April 10
7:30 am Continental Breakfast Breakout Discussions - View All Breakouts
8:30 Chairperson’s Remarks
8:35 Binding Kinetics and Thermodynamics to Understand and Enhance Selectivity of Kinase Inhibitors
Development of kinase inhibitors with outstanding selectivity remains a significant challenge with equilibrium selectivity of inhibitors for different kinases measured in biochemical assays being poorly translated under cellular and in vivo conditions. Measurement of kinetics and thermodynamics of kinase inhibitors provide distinct insights into the molecular determinants of selectivity, thereby facilitating the design of selective kinase inhibitors. The talk will cover these aspects of relevant data on some clinically used kinase inhibitors.
9:05 FEATURED PRESENTATION: Exploring the Hidden World of Non-Canonical Protein Phosphorylations
Phosphorylation of histidine, lysine and arginine, the so-called “hidden phosphoproteome”, is poorly characterized. To address this void, we developed monoclonal antibodies (mAbs) that selectively recognize the 1- and 3-isoforms of
9:35 Coffee Break in the Exhibit Hall with Poster Awards Announced
Poster Awards Sponsored by Domainex
10:30 Using Fragment-Based Lead Discovery (FBLD) for Kinase Inhibitor Development
In this talk, I will provide examples of how Astex is exploiting high throughput protein crystallography and fragment-based lead discovery (FBLD) for kinase inhibitor development.
10:50 A Kinase Platform for the Discovery of Reversible and Covalent Kinase Inhibitors
Protein kinases play an important role in signaling pathways that control cell growth, metabolism, proliferation
11:10 Novel Design Paradigms for Protein Kinases and Phosphatases – Binding Kinetics and Allosteric Mechanisms
We will demonstrate that a thorough understanding of the precise pharmacophoric requirements on the target’s binding site is essential to pre-engineer the desired slow off-rates into new, thus literature-unprecedented scaffolds that qualify as privileged structures for the target family of kinases.
11:30 Recent Experiences with Fragments for Kinases
Roderick Hubbard, DPhil, Professor and Senior Fellow, University of York and Vernalis
Fragments provide valuable tools for probing kinase biology and starting points for lead molecules. I will discuss results from three recently disclosed kinase collaborative projects: DYRK1A, PAK1, LRRK2. For DYRK1A, potent, in vivo active, selective inhibitors probed target biology; for PAK1,
12:00 pm Close of Conference