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Chemistry and Pharmacology of Drug Discovery
brain barrier more easily compared to monoclonal antibodies. Thus, tucatinib (1) offers a
promising therapeutic strategy for the treatment of HER-2-positive breast cancer with
improved treatment efficacy and safety in combination with trastuzumab and
capecitabine.
Figure 1. Chemical structure of HER2 tyrosine kinase inhibitors lapatinib (2) and
neratinib (3)
1 Background
Breast cancer is a second major cause of cancer-related mortality in women and HER2-
2
positive accounts for about 15–20% of all breast cancer patients.
In contrast to HER2-
negative breast cancer, HER2-overexpressing breast cancer has been related to aggressive
3
disease and low survival rates.
HER2 overexpression is also detected in other types of
human cancers, including bladder, colon, ovary, esophagus, stomach, lung, uterus, and
3,4
prostate cancer.
breast cancer possessing HER2 overexpression and/or amplification.
Thus, HER2 is an effective therapeutic drug target in patients with
3
During the last few decades, significant progress has been made in the
treatment of HER2-positive disease, especially in HER2-positive breast cancer. A series
of novel HER2-targeted agents have been developed that have remarkably improved the
prognosis of patients harboring HER2-positive breast cancer and extended their lives.
Currently, approved drugs for patients with HER2-positive breast cancer include the
5
following three classes:
(1) Monoclonal bodies, such as trastuzumab and pertuzumab.
(2) Antibody–drug conjugates (ADCs), such as trastuzumab deruxtecan (DS-8201) and
trastuzumab emtansine (T-DM1). (3) Small-molecule tyrosine kinase inhibitors (TKIs)
6
lapatinib
and neratinib.7 However, several clinic unmet needs exist in patients with
HER2-positive metastatic breast cancer. First, although the treatment of the patient with
trastuzumab could improve prognosis in patients with HER2-positive metastatic breast
cancer, primary and acquired resistance remains a significant clinical challenge in most
patients with HER2-amplified metastatic breast cancer. Second, adverse effect profiles
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Chapter 9. Tucatinib (Tukysa)
for small-molecule tyrosine kinase inhibitors, such as lapatinib (2) and neratinib (3),
display roughly equipotent inhibition activities against EGFR and HER2, which
possesses off-target adverse effects, including diarrhea and skin rashes, resulting from
8
EGFR inhibition.
Thus, the urgent clinic needs to develop novel tyrosine kinase
inhibitors that block HER2 activity with no inhibition activity against other EGFR
subfamily proteins to improve efficacy and safety.
Recently, tucatinib (1), developed by Seattle Genetics, received its first
approval in April 2020 for the treatment of unresectable or metastatic HER-2 positive
breast cancer in combination with trastuzumab and capecitabine. It was the first oral
HER2 tyrosine kinase inhibitor with a highly selective enzymatic activity against HER2
and EGFR (HER2 IC
= 6.9 nM; EGFR IC50 = 449 nM).1 This selectivity may improve
50
tolerability and efficacy compared to earlier HER2 inhibitors such as lapatinib (2) and
9
neratinib (3) which harbor common EGFR-associated toxicities (Figure 2).
2 Pharmacology
HER2 belongs to the HER family comprising four members, namely EGFR, HER2,
HER3, and HER4. These proteins structurally have an extracellular ligand-binding
domain, a single transmembrane domain, and a cytoplasmic catalytic tyrosine kinase
Figure 2. The HER2 signaling pathway
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Chemistry and Pharmacology of Drug Discovery
domain.10 The binding of HER proteins with their ligands triggers the formation of
homodimers and heterodimers, which upregulate downstream signaling pathways. Unlike
the other HER proteins, HER2 lacks a specific ligand and is the preferred partner for the
homodimerization and heterodimerization with itself or other HER proteins.
Subsequently, the homodimerization and heterodimerization of HER2 protein triggers the
activation of the kinase activity of the HER2, resulting in stimulation of downstream
signaling pathways, including activation of the Ras/MAPK and PI3K/AKT/mTOR
12
signaling pathways.
HER2-directed kinase inhibitors can compete with ATP, resulting in the
blockade of phosphorylation and preventing activation of downstream signaling
pathways. Tucatinib is the first high-selective HER2 kinase inhibitor, which reversibly
binds to the cytoplasmic catalytic kinase domain of the HER2 and competes with ATP,
preventing tyrosine phosphorylation and inhibiting downstream MAPK and AKT
signaling pathways. The recent data indicates the combination of tucatinib and
1
trastuzumab exhibited synergized improved anti-tumor activity in vitro and in vivo.
3 Pharmacokinetics and Drug Metabolism
Tucatinib tablets are available as 50 and 150 mg film-coated tablets, which can be taken
every 12 h with or without food in combination with trastuzumab. Tucatinib tablets were
recommended to be taken orally at a dosage of 300 mg until disease progression or
unacceptable toxicity appears. It should be taken regularly at the scheduled time, even if a
dose of tucatinib is vomited or missed. Furthermore, for the patient with severe hepatic
impairment, the dosage should be reduced to 200 mg orally twice daily.
When tucatinib was taken by oral administration, its t
h. After continuously using tucatinib 300 mg twice daily for 14 days, a steady state is
reached in approximately 4 days. As a result, the AUC increases by 1.7-fold while the
increases by 1.5-fold, respectively. With 97% plasma protein binding, the apparent
C
max
volume of distribution is 1670 L. The half-life (T
) of tucatinib is approximately 8.5 h.
1/2
After a 300 mg dose of tucatinib, approximately 86% of tucatinib is excreted in feces
(16% of tucatinib is unmetabolized) and 4% of it is excreted in urine. Although the
modestly rises 1.5-fold and the t
AUC
∞
is postponed from 1.5 to 4 h following a high-
max
fat meal, these changes are not clinically useful. Additionally, participants with severe
hepatic impairment had higher exposure to tucatinib than volunteers with mild
impairment (1.61- and 1.15-fold geometric mean ratio AUC
0→∞
Volunteers with modest hepatic impairment and those with normal hepatic function had
13
comparable tucatinib plasma concentrations.
13
was approximately 2
max
increases, respectively).
11
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Chapter 9. Tucatinib (Tukysa)
Figure 3. Predominant metabolic pathway of tucatinib (1)
A phase I clinic trial (NCT03758339) demonstrated that tucatinib (1) is
metabolized mainly by CYP2C8 and to a lesser degree by CYP3A. It is found that the
chief metabolite of tucatinib is ONT-993 (4), generated by CYP2C8-mediated
hydroxylation (Figure 3). It is shown that the cytotoxicity of ONT-993 (4) is 2- to 3-fold
less than that of tucatinib and its potency-adjusted exposure accounts for less than 10% of
the overall pharmacological activity. Therefore, ONT-993 (4) is not anticipated to
14
improve tucatinib’s safety or efficacy remarkably.
According to research on drug–drug interactions, patients are advised against
using potent CYP2C8 inhibitors along with tucatinib concurrently. Tucatinib (1) is
advised to be taken 100 mg twice daily if unavoidable using a strong CYP2C8 inhibitor
15
concurrently.
4 Efficacy and Safety
The safety of tucatinib (1) in combination with trastuzumab and capecitabine was
investigated in a randomized (2:1), double-blind, placebo-controlled clinical trial. The
patients with HER2-positive unresectable locally advanced or metastatic breast cancer
were selected for this clinical trial.
mg or placebo twice a day, regular dosages of trastuzumab either intravenously or
subcutaneously, and on days 1–14 of each 21-day cycle, oral capecitabine 1000 mg/m
A total of 612 individuals were randomly assigned to receive treatment with
trastuzumab and capecitabine (410 to tucatinib and 202 to placebo). The primary
outcome for the first 480 randomized patients was PFS as determined by a blinded
independent review committee. Tucatinib greatly improves the primary endpoint of
progression-free survival (PFS). For patients treated with tucatinib (1), trastuzumab, and
capecitabine, the median PFS was 7.8 months compared with 5.6 months for those
receiving placebo. Among the 612 patients in the trial, the group receiving tucatinib,
trastuzumab, and capecitabine had a median overall survival (OS) of 21.9 months, while
the group receiving placebo, trastuzumab, and capecitabine had a median OS of 17.4
8
months.
16
The study treatment consisted of oral tucatinib 300
2
.
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The safety of tucatinib (1) in combination with trastuzumab and capecitabine
was assessed in 601 patients with HER2-positive metastatic breast cancer who received at
least one dosage of study treatment on HER2CLIMB. The most common (incidence >
50%) all-grade adverse reactions include diarrhea (81%), palmar-plantar
erythrodysesthesia syndrome (63%) and nausea (58%). The most frequent grade 3–4
adverse reactions (incidence > 5%) include palmar-plantar erythrodysesthesia (13%),
diarrhea (13%), and hepatotoxicity (9%).
Chemistry and Pharmacology of Drug Discovery
17
5 Synthesis
The retro-synthetic analysis of tucatinib (1) is shown in Scheme 1. Tucatinib (1) is
assembled from fragments A, B, and C. Fragments A and B are connected by carbonnitrogen bonds via aromatic nucleophilic substitution (SNA). A cyclization connects
fragments 5 and 6. The fragment 5 could be synthesized from commercially available
aniline 11 by a condensation followed by a reduction reaction. On the other hand,
fragment 6 is connected by the S
from starting materials 15 by condensation followed by cyclization. There are two
connection methods to construct fragments A and B. One is to directly install fragment 8
Scheme 1. Retro-synthetic analysis of tucatinib (1)
Ar reaction of 9 with 10. Fragments 10 is assembled
N
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Chapter 9. Tucatinib (Tukysa)
into fragment B by SNAr reaction. The other is made by coupling 5 and 14 followed by
cyclization.
The first synthesis route for tucatinib (1) was reported by Array Biopharma in
18
First, the treatment of aniline 11 with N,N-dimethylformamide dimethyl acetal
2007.
(DMF–DMA) delivered formamidine 7 in 87% yield. It was followed by catalytic
hydrogenation reduction of the nitro group to give intermediate 5 in 90% yield.
Subsequently, the intermediate 5 was treated with the 1,1′-thiocarbonyl diimidazole
(TCDI) and 2-amino-2-methyl-1-propanol 14 at –10 °C for 16 h, leading to thiourea 12 in
34% isolated yield, which then performed an intermolecular [5 + 1] cycloaddition with
fragment 5 to give aminoquinazoline derivative 17 in 62% yield. Finally, tucatinib (1)
was obtained in 68% yield through an intramolecular cyclization by the treatment with ptoluenesulfonyl chloride (p-TsCl) and NaOH at room temperature. In summary, tucatinib
(1) was prepared in 16.3% yields in five steps from starting materials 5 (Scheme 2).
Mao and coworkers recently designed a convergent synthetic route for
synthesizing tucatinib (1, Scheme
methyl-4-nitrophenol 9 with 4-chloropyridin-2-amine 18 to give diaryl ether 19 in the
presence of DIPEA as a base at 150 °C for 72 h in 64% yield, followed by the reaction of
DMF–DMA and hydroxylamine hydrochloride to afford the formamidine 20.
Scheme 2. Array BioPharma’s synthesis route of tucatinib (1)
19
3).
At first, the SNAr nucleophilic substitution of 2-
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Subsequently, the cyclization of formamidine 20 in the presence of trifluoroacetic acid
anhydride (TFFA) to deliver the triazolopyridine 16. Next, the catalytic hydrogenation
reduction of the nitro group resulted in the intermediate 6 in 68% yield, followed by the
condensation with the N,N-dimethylphenylformimidamide 7 to give intermediate 21 in
83% yield. The catalytic hydrogenation reduction of the nitro group gave intermediate 22,
which underwent the substitution with dimethyl-2-(methylthio)-4,5-dihydrooxazole 8 to
give 1 in 76% yield. In summary, it takes seven steps to furnish the final product 1 with
an overall 19.0% yield.
Chemistry and Pharmacology of Drug Discovery
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Chapter 9. Tucatinib (Tukysa)
Scheme 3. Mao’s synthetic route to tucatinib (1)
Mao and coworkers recently developed a practical process for preparing
20
4).
tucatinib (1, Scheme
Shortly, the condensation of 4-chloropyridin-2-amine (18) with
DMF–DMA, followed by the treatment with hydroxylamine hydrochloride, leading to the
N-hydroxy-formimidamide 23 in 89% yield. Subsequently, compound 23 was subjected
to TFAA, giving the triazolo[1,5-a]pyridine derivative 24 in 71% yield. Next, the
nucleophilic substitution of 4-amino-2-methylphenol (25) with compound 24 in
DMF/K
at 130–140 °C for 16 h, to deliver intermediate 6 in 73% yield. The
2CO3
subsequent cyclization reaction was conducted by heating 6 and 11 with acetic acid to
furnish compound 21, followed by catalytic hydrogenation to afford aniline 22.
Subsequently, compound 22 reacted sequentially with TCDI and 2-amino-2-methyl-1propanol 14 in DMF for 4 h, and compound 17 was obtained in 81% yield. Finally, 17
was treated with NaOH and p-TsCl in THF at 50–60 °C for 3 h to give tucatinib (1) in
77% yield.
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Chemistry and Pharmacology of Drug Discovery
6 Summary
In summary, tucatinib (1) is an orally bioavailable, selective HER2 inhibitor, developed
by Seattle Genetics and received its approval in April 2020 for the treatment of HER2
positive breast cancers. Compared to lapatinib and neratinib associated with
gastrointestinal and dermatologic adverse effects, tucatinib displays high selectivity
against HER2, with improved tolerability and efficacy. However, the clinical
applicability of reversible HER2 TKIs is limited due to clinical resistance caused by the
HER2 mutation.
strategy for the novel treatment of HER2-positive breast cancers in the future.
Scheme 4. Mao’s synthetic route to tucatinib (1)
21
Therefore, targeted protein degradation may emerge as an alternative
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Chapter 9. Tucatinib (Tukysa)
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