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Chemistry and Pharmacology of Drug Discovery
pharmacokinetics and pharmacodynamics studies, alongside safety and efficacy
evaluations from dose escalation studies.
The drug’s mean absolute oral bioavailability stands at 33%. Postadministration, tazemetostat (1)’s C
(maximum plasma concentration) is achieved
max
within a 1–2-h window, and its average half-life spans 3–4 h. Its primary metabolic
pathway involves N-dealkylation via CYP3A, leading to the formation of metabolites
EPZ-6930 (28, resulting from the loss of tetrahydropyran) and EPZ-6931 (29, through deethylation). In some instances, the drug loses both N-alkyl functionalities. These
metabolites, however, are considerably less potent, translating to negligible
13, 14
pharmacological effects in vivo.
Elimination predominantly occurs through fecal excretion (79%) and, to a lesser
extent, via urine (15%) over a 12-day period. Tazemetostat (1) has a substantial apparent
volume of distribution (V
) at 1230 L, indicating extensive distribution into body tissues.
d
In vitro studies have shown that the drug is 88% bound to human plasma proteins. As a
significant substrate of CYP3A, tazemetostat (1) has potential drug–drug interaction
(DDI) risks when co-administered with other CYP3A inhibitors or inducers.
Additionally, it acts both as a substrate and an inhibitor of P-gp; hence, the concurrent
use of tazemetostat (1) with P-gp
exposure remains largely unaffected by a high-fat meal.
inhibitors is not recommended. Notably, the drug’s
15
5. Efficacy and Safety
In preclinical evaluations, the in vivo efficacy of tazemetostat (1) was consistently
demonstrated across multiple tumor xenograft models, highlighting its potential
therapeutic application. Tazemetostat (1) showcased excellent selectivity over other
enzyme, especially over 30-fold selectivity for EZH1, underscoring its targeted
mechanism of action.
Transitioning to clinical investigations, tazemetostat’s (1) promising preclinical
efficacy transferred well in human subjects. An initial phase I study assessed both the
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Chapter 10. Tazemetostat (Tazverik)
safety and efficacy of tazemetostat (1) as a standalone treatment in patients with relapsed
or refractory (R/R) non-Hodgkin lymphoma and those at high-risk for solid tumors.
During the dose-escalation phase, tazemetostat (1) dosages ranged between 100 and
1600 mg, administered twice daily. Based on an assessment of the overall response and
safety data, a subsequent expansion cohort received an optimized dose of 800 mg, again
twice daily (n = 64). Importantly, tazemetostat (1) was well-tolerated: the predefined
13
maximum tolerated dose threshold was not reached, emphasizing its safety profile
.
Following this, a phase II trial was initiated, involving 99 R/R Follicular
Lymphoma patients, each having undergone at least two prior therapeutic regimens.
mut
Distinct response rates were observed: in the EZH2
objective response rate (ORR), while in the EZH2
cohort (n = 45), a significant 69%
wild
group (n = 54), the ORR stood at
35%, which suggests the adoption of this biomarker to determine whether use this drug.
The median response duration reached 10.9 months in the EZH2 mutant cohort, with
several patients progressing from a partial to a complete response upon extended
16
treatment.
Such compelling outcomes underline the potential of EZH2 inhibition as a
strategy for managing challenging cases of follicular lymphoma.
It is noteworthy that the combination of tazemetostat (1)’s minimal treatmentrelated adverse events and the robust efficacy data from this trial persuaded the FDA to
grant marketing approval in 2020—even before the initiation of a pivotal phase III
clinical trial. As of the latest updates, tazemetostat (1)’s
efficacy is under evaluation
across a spectrum of cancers, including epithelioid sarcoma (ES), metastatic castrationresistant prostate cancer (mCRPC), and diffuse large B-cell lymphoma (DLBCL). While
approvals have been secured for specific indications, others remain under rigorous
14, 17, 18
clinical scrutiny.
6. Synthesis
The synthesis of tazemetostat (1) employs a convergent approach, involving the
preparation and subsequent coupling of three distinct molecular fragments through amide
coupling and Suzuki coupling. This synthetic route not only is pivotal in the medicinal
chemistry development of tazemetostat (1) but also plays a critical role in its
manufacturing process.
The synthesis begins with the commercially available 2-methyl-3-nitrobenzoic
acid (30). After bromination with dibromatin, the resulting compound 31 is then
subjected to methylation to protect the carboxylic acid. This step involves treating the
carboxyl group with Na
Then the nitro group of the methyl benzoate derivative is reduced to an amine using Fe
and NH
Cl. This reduction yields the amine compound 33.
4
12, 19
and CH3I, resulting in a methyl benzoate derivative 32.
2CO3
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Chemistry and Pharmacology of Drug Discovery
The formation of the tertiary amine core of tazemetostat (1) is constructed
through two consecutive reductive amination reactions. These two steps conducted under
standard reductive amination reaction condition employing NaBH(OCOCH
as the
3)3
reducing agent to achieving 35. Following the dual reductive amination strategies, a basepromoted ester hydrolysis was employed, leading to the formation of the first fragment
36, which encompasses both bromide and carboxylic acid functional groups for later
coupling.
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The second fragment 37, which bears an amine moiety is then coupled to the
benzoic acid core through the amide coupling reaction, which install the warhead toward
EZH2. This step achieves a 74% yield when using PYBOP as the coupling reagent.
The final step in the synthesis of tazemetostat (1) is marked by a Suzuki
coupling reaction. This reaction couples compound 39 and corresponding boronic ester
40 using Pd(PPh3)4. The successful execution of this reaction results in the formation of
tazemetostat (1) in 71% yield.
Chapter 10. Tazemetostat (Tazverik)
In summary, the medicinal chemistry route for tazemetostat (1) is a multistep,
convergent process that efficiently assembles the drug through strategic fragment
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couplings and a series of chemical transformations. This route not only demonstrates the
intricacies of organic synthesis but also underscores the importance of each step in
achieving the final therapeutic molecule with high purity and yield.
Chemistry and Pharmacology of Drug Discovery
7. Summary
The development of tazemetostat (1), a pioneering EZH2 inhibitor, highlights the
enduring importance of molecular conformation in drug discovery. This principle is
crucial not only for tazemetostat (1) but also forms a cornerstone in the creation of
numerous effective therapeutic agents. The strategic manipulation of molecular
conformation plays a key role in enhancing drug properties such as potency and
selectivity.
While the concept of molecular conformation has been known for decades,
recent advancements in computing power have provided an additional tool, making the
analysis and prediction of molecular shapes more accessible. This enhancement in
computational capabilities allows for more sophisticated modeling of drug–target
interactions, offering valuable insights that guide the drug development process.
However, it is important to note that this is just one aspect of a much broader and
multifaceted approach.
The journey of tazemetostat (1), particularly through the “magic methyl” effect,
demonstrates how subtle structural modifications can significantly alter a drug’s efficacy
profile. In conclusion, molecular conformation remains a fundamental aspect of drug
discovery, essential for the development of new and improved therapies. The modern era,
with its advanced computational tools, offers exciting opportunities to deepen this
understanding, and the core principles of medicinal chemistry continue to guide this everevolving field.
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Section III. CNS DRUGS
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________________________________________________________________________________
Ozanimod (Zeposia): An S1P Receptor
Modulator for Treating Multiple Sclerosis and
Inflammatory Bowel Diseases
Shaohui Yu and
Xi Wang
1. Background
1.1. MS and IBD
One of the most remarkable properties of the immune system is its ability to distinguish
between self-cells and foreign cells. In some individuals, there’s a flaw in the process and
autoimmune disease occurs because of the inappropriate self-attack.
Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous
system (CNS). In MS, myelin which is the fatty tissue that protects nerve fibers, is
attacked upon immune cell activation forming scar tissues called sclerosis.
the nerves are damaged and lose the ability to conduct electrical impulses to and from the
brain, triggering progressive neurodegeneration of the brain and spinal cord. MS is
typically present in young adults with the average onset age between 20 and 30 years.
Common symptoms of MS include fatigue, depression, bowel and bladder dysfunction,
Chemistry and Pharmacology of Drug Discovery, First Edition. Edited by Jie Jack Li.
© 2025 John Wiley & Sons, Inc. Published 2025 by John Wiley & Sons, Inc.
1
2,3
As a result,
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