KIC

Cambridge Healthtech Institute 第9届

Kinase Inhibitor Chemistry

( 激酶抑制剂化学 )

发现与设计激酶抑制剂的新方法

2018年4月3-4日 | Hilton Bayfront | 加州圣地牙哥

 

在过去十年间,激酶抑制剂的药物开发造就了一个新世代抗癌药物的快速发展。激酶抑制剂的开发依然活跃,且在创药领域占有显要地位,科学家们找到了新方法去拓展人类激酶体中更为深入的标的领域,研发重点不再限于癌症,而向中枢神经系统疾病等慢性疾病以及异位调节方面转移,在长时间滞留及不可逆化合物的利用方面有了重大进展。

本研讨会将聚集在大学及药厂担任指导角色的研究人员,在构筑人脉及合作关系的同时,也会针对激酶抑制剂创药领域的研究进展状况交换意见。


Final Agenda

Tuesday, April 3

7:00 am Registration and Morning Coffee

OPTIMIZING NEXT-GENERATION KINASE INHIBITORS

8:00 Welcome Remarks

Kip Harry, Senior Director, Conferences, Cambridge Healthtech Institute

8:05 Chairperson's Opening Remarks

Gerhard Mueller, PhD, CSO, Gotham Therapeutics


8:10 FEATURED PRESENTATION: Selective Targeting of Kinase Catalytic and Non-Catalytic Function

Stefan Knapp, PhD, Professor, Department of Pharmaceutical Chemistry, Goethe Institut, Frankfurt

Advances in kinase structural biology led to an excellent structural coverage of the human kinase family and provided insight into the remarkable domain plasticity of the catalytic domain. Our laboratory contributed 75 of the currently ~200 known crystal structures, enabling a family-wide structural analysis for rational design of inhibitors. In this talk I will summarize strategies that led to the development of highly selective inhibitors. I will discuss the discovery of novel inhibitor binding sites including allosteric sites and the exploitation of unusual structural features for the design of highly selective kinase inhibitors.

8:40 Structure-Based Design of Long Residence Time into Novel Kinase Inhibitors

Gerhard_MuellerGerhard Mueller, PhD, CSO, Gotham Therapeutics

The presentation focuses on the engineering of binding kinetic signatures into "deep-pocket-directed" scaffolds for achieving high-efficacy kinase inhibitors. 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.

9:10 Sponsored Presentation (Opportunity Available)

9:40 Coffee Break

10:05 Target Residence Time-Guided Optimization of TTK Kinase Inhibitors

Guido_ZamanGuido J.R. Zaman, PhD, Managing Director & Head of Biology, Netherlands Translational Research Center B.V. (NTRC)

We studied NTRC 0066-0, a selective inhibitor of TTK, together with eleven TTK inhibitors from different chemical classes developed by others. Parallel testing showed that the cellular activity of the TTK inhibitors correlates with their binding affinity and, more strongly, with target residence time. X-ray structures revealed that the most potent inhibitors induce a unique structural conformation. Based on this insight, new TTK inhibitors were developed with longer target residence times and very potent anti-proliferative activity.

10:35 Comparison of Methods for Determination of Drug-Target Engagement in Live Cells

Aleksandra_BaranczakAleksandra Baranczak, PhD, Senior Scientist, Discovery Chemistry and Technology, AbbVie

While the list of potential techniques that enable studies of target engagement is continuously expanding, identification of the best method to evaluate interactions between a ligand and its cellular binding partner(s) remains far from straightforward. We will discuss the applicability of various methods for determining target engagement of reversible and irreversible inhibitors of soluble and membrane kinases in live cells. The strengths and limitations of all methods will be analyzed, as well as their adaptability to high-throughput format assay development.

11:05 Determination of a Focused Mini-Kinase Panel for Early Identification of Selective Kinase Inhibitors

Scott_BembenekScott Bembenek, PhD, Principal Scientist, Computer-Aided Drug Discovery, Janssen Research & Development

Currently, a rational, systematic, and unbiased method for choosing such a mini-kinase panel that reliably determines a compound's kinase selectivity profile does not exist. Using a novel in-house deconvolution algorithm, we performed a comprehensive analysis on our extensive kinase data set that has yielded findings far beyond those in the current literature. Indeed, one can construct a mini-kinase panel of optimal size that is very predictive when compared to the corresponding full kinase panel. Comparing this mini-kinase panel to random selection, we find an enrichment of 45.1%.

11:35 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

12:20 pm Session Break

ADVANCES IN COVALENT INHIBITOR DEVELOPMENT

1:15 Chairperson's Remarks

Stefan Laufer, PhD, Chairman, Pharmaceutical & Medicinal Chemistry, Pharmacy & Biochemistry, University of Tuebingen

1:20 Highly Selective JAK3-Inhibitors with a Covalent-Reversible Binding Mode Targeting a Nitrile-Induced Arginine Pocket

Stefan_LauferStefan Laufer, PhD, Chairman, Pharmaceutical & Medicinal Chemistry, Pharmacy & Biochemistry, University of Tuebingen

JAK3 functions are restricted to immune cells, suggesting it as a primary target. However, the high degree of structural conservation makes isoform selective targeting a challenging task. Here we present picomolar inhibitors with unprecedented selectivity for JAK3. Selectivity was achieved by concurrent covalent-reversible targeting of a JAK3-specific cysteine residue and a novel induced binding pocket yielding versatile tool compounds for the elucidation of JAK3 specific functions.

1:50 The Meisenheimer Complex as a Novel Paradigm in Drug Discovery: Targeting PLK1 through a Novel Covalent Mechanism

Campbell_MclnnesCampbell McInnes, PhD, Professor, Drug Discovery and Biomedical Sciences, University of South Carolina

We will describe novel inhibitors of PLK1 kinase activity that inhibit through a unique covalent strategy. The discovery and optimization of these inhibitors is described in addition to confirmation of their on-target anti-tumor mode of action through selective PLK1 inhibition.

2:20 Presentation to be Announced


2:50 FEATURED PRESENTATION: Discovery of the Covalent FGFR1-4 Inhibitor PRN1371 for the Treatment of Solid Tumors

Michael Bradshaw, PhD, Associate Director, Principia Biopharma

We have developed a selective, irreversible covalent inhibitor of FGFR1-4, PRN1371, by targeting a cysteine residue within the kinase domain. PRN1371 demonstrates highly selective and long lasting inhibition of FGFR which extends beyond drug clearance from circulation. Strong inhibition was also sustained toward clinically relevant FGFR mutations and translocations. In addition, durable tumor regression was obtained in multiple rodent xenograft models and was sustained even using an intermittent dosing strategy that provided drug holidays. PRN1371 is currently in a Phase I clinical trial for the treatment of solid tumors.

3:20 Sponsored Presentation (Opportunity Available)

3:35 Refreshment Break in the Exhibit Hall with Poster Viewing

4:30 Plenary Session Welcome Remarks from Event Director

Anjani Shah, PhD, Conference Director, Cambridge Healthtech Institute

4:35 Plenary Keynote Introduction

Kevin Lustig, PhD, CEO, Scientist.com


4:40 PLENARY KEYNOTE: Targeting Ras and MYC for the Treatment of Cancer

Stephen Fesik, PhD, Professor of Biochemistry, Pharmacology, and Chemistry, Orrin H. Ingram II Chair in Cancer Research, Vanderbilt University School of Medicine

Two of the most important targets in cancer are Ras and MYC. However, both of these highly validated cancer targets are thought to be undruggable. In this presentation, I will discuss our approaches for targeting both of these proteins directly and indirectly using fragment-based methods and structure-based design.

5:30 Welcome Reception in the Exhibit Hall with Poster Viewing

6:30 End of Day

Wednesday, April 4

7:30 am Continental Breakfast Breakout Discussions

DESIGN AND DEVELOPMENT OF NOVEL ALLOSTERIC MODULATORS

8:30 Chairperson's Remarks

Ravi G. Kurumbail, PhD, Research Fellow and Structural Biology Laboratory Head, Pfizer

8:35 Fragment-Based Discovery of Inhibitors of ERK Kinase

Marc O'Reilly, PhD, Senior Director of Molecular Sciences, Astex Pharmaceuticals

This work describes the discovery of highly selective, orally bioavailable, allosteric/bitopic inhibitors of ERK kinase which show robust anti-tumor activity in a range of animal models.

9:05 Isoform-Selective Activators of AMP-Activated Protein Kinase for Metabolic Diseases

Ravi_KurumbailRavi G. Kurumbail, PhD, Research Fellow and Structural Biology Laboratory Head, Pfizer

AMP-activated protein kinase (AMPK) is a heterotrimeric protein kinase that maintains cellular and whole-body energy homeostasis. We have been seeking specific activators of AMPK for the treatment of cardiovascular and metabolic diseases. High-throughput screening using a novel biochemical assay platform resulted in the identification of multiple chemotypes that target distinct AMPK subunits. We have established the molecular mode of action of these isoform-selective activators through structural, biophysical and kinetic studies.

9:35 Coffee Break in the Exhibit Hall with Poster Viewing

KINASE INHIBITORS FOR CNS AND NEURODEGENERATIVE DISORDERS

10:30 Optimization of Brain Penetrant ATM Kinase Inhibitors for the Treatment of Huntington's Disease

Leticia_Toledo-ShermanLeticia Toledo-Sherman, PhD, Director of Computer-Aided Drug Design and Medicinal Chemistry, Chemistry, CHDI Foundation

The presentation will be centered on our efforts to attain potent, selective and brain penetrant ATM kinase inhibitors as proof-of-concept agents for HD. Importantly we demonstrate strong in vitro-in vivo correlations and a robust PK/PD relationship that warrant further studies with these compounds.

11:00 A Journey in the Kinome: Approaches, Strategies and a Bit of Luck

Daniele Andreotti, Director, Head, Medicinal Chemistry 3; Drug Design and Discovery, Aptuit

11:30 Discovery of 7-Oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine Derivatives as Potent, Orally Available, and Brain-Penetrating Receptor Interacting Protein 1 (RIP1) Kinase Inhibitors - Analysis of Structure-Kinetic Relationships

Masato Yoshikawa, PhD, Principal Scientist, CNS Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited

We will present a discovery of 7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine derivatives as a novel chemical series of brain-penetrating RIP1 kinase inhibitors. The optimization by utilizing SBDD approach led to the discovery of a highly potent, orally active, and brain-penetrating RIP1 kinase inhibitor with excellent PK profiles. Our preclinical candidate significantly suppressed necroptotic cell death both in mouse and human cells. Oral administration of the candidate (10 mg/kg, bid) attenuated disease progression in the mouse EAE model of multiple sclerosis.

12:00 pm End of Conference

* 活动内容有可能不事先告知作更动及调整。