Drug Metabolism and Pharmacokinetics (eBook)

Frontiers, Strategies, and Applications

Liang Shen (Herausgeber)

eBook Download: EPUB

2025
1105 Seiten
Wiley (Verlag)
978-1-394-30013-6 (ISBN)

Infos

Practical, state-of-the-art pharmacokinetic research methods, ideas, advancements, applications, and strategies

Drawing on a wealth of extensive practical experience and theoretical research, Drug Metabolism and Pharmacokinetics encapsulates the most recent advancements and illustrative applications in the field. Sixty-eight relatively independent yet interconnected articles are included, each offering a unique perspective and providing in-depth interpretation. Readers can either read systematically or select specific topics of interest from the table of contents.

Basic concepts, frontier advancements, DMPK research strategies, and technical methods are covered for novel drug modalities and therapeutics in different disease areas. The book encompasses a wide range of application and validation cases for DMPK research, including studies in in vitro ADME, in vivo pharmacokinetics, metabolite profiling and identification, radiolabeled ADME, and bioanalysis. Case studies showing the application of topics covered are included throughout, along with valuable insights into problem-solving and critical thinking.

Written by a team of scientists specializing in DMPK research from the DMPK Department of WuXi AppTec, Drug Metabolism and Pharmacokinetics discusses sample topics including:

• ADME properties, metabolite identification, and bioanalytical strategies for oligonucleotide drugs
• Strategies and challenges in the determination of drug-to-antibody ratio (DAR) values of antibody-drug conjugates (ADCs)
• Breaking barriers in CNS drug development with intrathecal and intracerebroventricular administration
• Application and detection techniques of biomarkers in drug development
• Flux dialysis method for assessing plasma protein binding of high protein-binding drugs

Drug Metabolism and Pharmacokinetics is an essential forward-thinking reference on the subject for pharmacy students, pharmaceutical industry researchers, and DMPK scientists, especially those exploring novel drug modalities.

Liang Shen, PhD, is the head of DMPK at WuXi AppTec.

Textauszug

1
Proteolysis‐Targeting Chimeras (PROTACs)

1.1 An Overview of PROTAC Technology and Drug Metabolism and Pharmacokinetic (DMPK) Research Strategies

Chengyuan Li, Yu Wang, Jing Jin

1.1.1 Introduction

In recent decades, significant advances have been achieved in the development of new therapeutic approaches. Proteolysis‐targeting chimera (PROTAC) offers a new approach to some disease treatments, which has increasingly attracted the attention of drug developers in the last five years. Additionally, PROTAC, as a new therapeutic technology, has facilitated substantial investment worldwide. In this chapter, we summarized the PROTAC’s structure and mechanism of action, its global landscape, the drug metabolism and PK (DMPK) challenges in PROTAC research, and corresponding potential solutions.

1.1.2 Structure and Mechanism of Action of PROTACs

PROTAC utilizes the body’s natural protein degradation mechanism, known as the ubiquitin–proteasome system [1]. PROTAC is a bifunctional molecule that consists of three key structural parts: a ligand that binds the target protein, a ligand that binds the ubiquitin–protein ligase (E3), and a linker that connects the two ligands (Figure 1.1).

Because of its unique structure, PROTAC brings the E3 ligase and the target protein to proximity, which induces the E3 ligase to label the target protein with ubiquitin. This causes the target protein to degrade [2]. The PROTAC molecules that detach after the degradation of the target protein can be recycled (Figure 1.2). In contrast to the occupancy‐driven pharmacology of most small‐molecule drugs, PROTAC can access proteins that were previously inaccessible without occupying an active pocket or relying on target occupancy to disrupt the function of the target protein. This is known as event‐driven pharmacology.

Therefore, PROTAC offers many advantages in drug discovery:

• It has the potential to target many undruggable protein targets that lack active sites.
• While retaining the advantage of directly targeting intracellular proteins, it has the potential to overcome some of the disadvantages of small molecules such as drug resistance.
• To improve patient compliance, it can be administered orally.

Figure 1.1 Schematic of typical PROTAC structure.

Figure 1.2 Mechanism of action of PROTAC.

1.1.3 PROTAC Landscape Analysis

By using the event‐driven pharmacology, PROTAC offers an attractive therapeutic concept to control target protein levels. Although this is a relatively new modality, it has made rapid progress in the drug discovery pipeline.

1.1.3.1 PROTAC Research and Development Progress: International Pharmaceutical Companies

PROTAC has boomed in the last three years with Arvinas’ two candidate molecules, ARV‐110 and ARV‐471, being the first to demonstrate positive clinical data. In addition, ARV‐766, the company’s third PROTAC molecule, is set to enter the clinical phase. Other international companies, such as Kymera Therapeutics, C4 Therapeutics, and Nurix Therapeutics, that focus on developing protein degraders have a molecule in clinical phase I as well. In addition, other pharmaceutical companies such as Bristol‐Myers Squibb, Dialectic Therapeutics, and Accutar Biotechnology also own a PROTAC molecule in clinical phase I (Table 1.1).

Table 1.1 PROTAC research and development progress of some international pharmaceutical companies.

Company	PROTAC	Indications	Target	Study phase

Arvinas, Inc.

ARV‐471

Breast cancer (ER+/HER2‐breast cancer)

Estrogen receptor (ER)

Clinical phase III

ARV‐393

B‐Cell Malignancies

B‐cell lymphoma 6 protein (BCL6)

Clinical phase I

ARV‐102

Parkinson’s Disease Progressive Supranuclear Palsy

Leucine‐rich repeat kinase 2 (LRRK2)

Clinical phase I

Nurix Therapeutics, Inc.

NX‐2127

B cell malignancies

BTK + IMiD activity

Clinical phase I

NX‐1607

Immuno‐oncology

CBL‐B

Clinical phase I

NX‐5948

B cell malignancies and autoimmune diseases

BTK

Clinical phase I

Kymera Therapeutics, Inc.

KT‐474

Allergic dermatitis, hidradenitis suppurativa, rheumatoid arthritis

Interleukin‐1 receptor‐associated kinase 4 (IRAK4)

Clinical phase II

KT‐621

Immunology

STAT6

Clinical phase I

KT‐333

Solid tumors

STAT3

Clinical phase I

KT‐253

Solid tumors

MDM2

Clinical phase I

C4 Therapeutics, Inc.

CFT7455

Relapsed/refractory non‐Hodgkin’s lymphoma or multiple myeloma

IKZF1/3

Clinical phase I/II

CFT8919

Non‐small cell lung cancer (NSCLC) with drug‐resistant EGFR mutation

EGFR L858R

Clinical phase I

CFT1946

V600 mutant cancers

BRAF V600

Clinical phase I/II

Bristol‐Myers Squibb

AR‐LDD

Prostate cancer

AR

Clinical phase I

Dialectic Therapeutics, Inc.

DT‐2216

Tumor

BCL‐XL

Clinical phase I

Accutar Biotechnology Inc.

AC0699

Breast cancer

ER

Clinical phase I

AC0682

Breast cancer

ER

Clinical phase I

Ac176

Prostate cancer

AR

Clinical phase I

AC0676

Autoimmunity

BTK WT & C481S

Clinical phase I

Note: The information was obtained from the official websites of the companies mentioned in the table and the deadline for information collection is 15 December 2024.

(Only research pipelines with compounds are listed.) Vividion Therapeutics, ERASCA, and other PROTAC companies do not disclose pipeline information.

Table 1.2 PROTAC R&D progress of Chinese pharmaceutical companies.

Company	PROTAC	Indications	Target	Study phase

Lynk Pharmaceuticals Co., Ltd.

LNK01002

Hematological tumor

—

Clinical phase I

Kintor Pharmaceutical Limited

GT20029

Androgenetic alopecia, acne

AR

Clinical phase II

Haisco Pharmaceutical Group Co., Ltd.

HSK29116

B‐cell malignancies

BTK

Clinical phase I

BeiGene Ltd.

BGB‐16673

B‐cell malignancies

BTK

Clinical phase I

Cullgen Inc.

CG001419

Solid tumor

TRK

Clinical phase I/II

Hinova Pharmaceuticals, Inc....

Produkt-Details

• Erscheint lt. Verlag: 3.6.2025
• Sprache: englisch
• Themenwelt: Naturwissenschaften ► Chemie
• Schlagworte: antibody drug conjugate • bioanalysis • Biomarkers • DMPK • drug development • drug interactions • Drug metabolism • Drug research • in vitro ADME • in vivo pharmacokinetics • Macromolecules • metabolite identification • Oligonucleotide • peptide drug • pharmaceuticals • Pharmacokinetics • PK study • radiolabeled compounds
• ISBN-10: 1-394-30013-1 / 1394300131
• ISBN-13: 978-1-394-30013-6 / 9781394300136