Targeted Protein Degradation to Advance Oncology Drug Discovery

Описание: Featured Speakers: Behnam Nabet, PhD (Fred Hutchinson Cancer Research Center), and Matthew Stokes, PhD (Cell Signaling Technology)
ℹ️ Solutions for Oncology Discovery: https://cst-science.com/p79rm9

Targeted protein degradation (TPD) is an emerging research strategy centered around using small molecules called “degraders” to trigger ubiquitin-dependent degradation of specific proteins. This approach shows promise for oncology drug development for many reasons, including the ability to selectively disrupt critical signaling pathways, target previously inaccessible cancer-causing proteins, and overcome drug resistance. Degradation-based strategies also complement basic genetic experiments while offering better target selectivity and enabling functional studies with superior kinetic resolution. Proteomics approaches often work in concert with degradation-based technologies, enabling the discovery of biomarkers, potential therapeutic targets, and a better understanding of therapeutic response across the whole proteome. In this webinar, the speakers will discuss strategies to target oncogenic signaling networks via selective control of protein homeostasis, while highlighting the impact of this approach on cancer therapeutics research.

During the webinar, viewers will:

● Learn how advances in targeted protein degradation can harness a cell’s degradation machinery to break down key cancer proteins
● Discover proteomics methods that can help discover new therapeutic targets and provide an array of kinome or proteome response data
● Hear about methods to selectively disrupt and analyze critical cancer signaling pathways

Contents:
0:00 Introduction
2:21 Customized Proteomics Solutions to Enable Discovery Research
3:26 Motif/PTM Antibodies
4:22 PTM profiling in biological samples
5:31 Discovery proteomics: Tyrosine phosphorylation
8:24 Behnam Nabet introduction
12:09 Targeted protein degradation
14:20 Co-opting an E3 ligase to induce targeted protein degradation
15:11 Prioritizing degradable kinases
16:53 Rationale for degrading FAK
19:11 Towards development of a selective FAK PROTAC
21:45 BSJ-04-146 potently degrades FAK and diminishes AKT signaling
23:27 Differential impact on phospho-signaling upon FAK degradation
24:41 FAK degradation diminishes viability in 3D-culture models
25:44 BSJ-04-146 leads to durable FAK degradation in vivo
28:14 Co-opting an E3 ligase to induce targeted protein degradation
29:43 The degradation tag (dTAG) system
31:12 Components of the dTAG system
33:26 Lead CRBN- and VHL-recruiting dTAG molecules
34:28 dTAG-13 degrades FKP12 F36V-fusions and requires CRBN
36:25 Rationale for targeting KRAS signaling in pancreatic cancer
38:11 Degradation relieves the oncogenic effects of KRAS
39:58 KRAS G12V degradation collapses cellular transcription signaling
42:25 Identification and targeting of vulnerabilities in cancer
44:14 DCLK1 is downstream of mutant KRAS and upregulated in PDAC progression
45:14 Development of a highly selective DCLK 1/2 inhibitor
47:23 Identification and evaluation of challenging drug targets
48:34 Achieving potent degradation in vivo
50:00 Generation of a conditional knock-in dTAG mouse
50:21 dTAG-mediated degradation of KRAS G12V in vivo
51:04 Summary: dTAG
53:03 Are there characteristics that make a for a good candidate for targeted protein degradation?
55:30 Are there any targets that are not good candidates?
57:35 The "hook effect" when increasing PROTAC concentration
59:06 Can a motif antibody differentiate when a nearby residue is phosphorylated?
61:53 Can glycosylation modifications be identified?
62:02 Do degraders obey predictable dose-response relationships?
63:01 What assays are used to evaluate the efficacy of a PROTAC?
65:40 What do you see as the future of targeted protein degradation?

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