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Chemistry and Pharmacology of Drug Discovery
5 Efficacy and Safety
In the preclinical study, pacritinib (1) potently blocked JAK/STAT signaling pathway,
induced apoptosis, and effectively abridged neoplastic cell proliferation in a dosedependent manner. Pacritinib
SET-2 and BaF3 xenograft model with resolution of hepatosplenomegaly in the absence
of hematologic toxicities such as anemia or thrombocytopenia or leukopenia and
prolonged
survival.
In phase I/II trial (NCT00719836), pacritinib (1) demonstrated promising
clinical activity in patients
20
malignancies.
In phase I dose-escalation component, adults with advanced myeloid
malignancies were treated with once-daily (qd) pacritinib
Among the several dose levels tested, there was a less than proportionate increase in
systemic exposure at doses from 100 to 400 mg, with negligible increase in
exposure >400 mg daily. Therefore, 400 mg daily (qd) was identified as the
recommended phase II dose for further evaluation.
In the phase I study, the majority of the patients (86%) experienced clinical
benefit. In patients with myelofibrosis, the clinical benefit rate was 94% (vs 43% in
patients with acute myeloid leukemia). In the phase II study pacritinib
promising result: 23.5% of evaluable patients achieved a spleen volume reduction of
35% by MRI from baseline to week 24.20 However, phase III studies of pacritinib (1),
PERSIST-1 and PERSIST-2, were placed on hold by the FDA in February 2016 due to
due to concerns over interim survival results, bleeding, and cardiovascular events.
hold was removed by FDA on January 5, 2017, upon review of the final phase III
PERSIST-1 data, final data from the phase III PERSIST-2 study, and planned dose
comparison protocol in patients with failure of prior JAK2-directed therapy.
Phase III PERSIST-2 randomized 311 patients with baseline thrombocytopenia
(platelet count ≤ 100 × 109/L) to pacritinib
BAT (45% received ruxolitinib). Combined analysis of patients on both pacritinib
arms found improved rates of ≥35% spleen reduction compared to BAT (18% vs 3%,
p = 0.001) based on computed tomography (CT) or magnetic resonance imaging (MRI).
Pacritinib
(1) 200 mg twice daily was most effective at improving hemoglobin levels and
reducing the transfusion burden. Plans are currently underway to launch the randomized
phase III PACIFICA trial in patients with severe thrombocytopenia (platelet
count 50 × 109/L) comparing pacritinib
≤
The most common adverse reactions of pacritinib
diarrhea, thrombocytopenia, anemia, nausea, and peripheral enema. The most frequent
serious adverse reactions included pneumonia, cardiac failure, disease progression,
pyrexia, and squamous cell carcinoma of skin.
(1) recapitulated these results in a JAK2 V617F-dependent
with myelofibrosis and other advanced myeloid
(1) 100–600 mg (n = 43).
21
(1) showed
≥
22
This
23
(1) 200 mg twice daily, 400 mg daily, and
(1)
(1) 200 mg daily vs physician’s choice.
(1) in the clinical trials were
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Chapter 8. Pacritinib (Vonjo)
6 Synthesis
The synthesis of pacritinib (1) was first disclosed in the patent published in 2007.24 Later
in 2011, the modified synthesis of pacritinib (1) was published in the J. Med. Chem. by
William et al. from the same company.
was synthesized by Suzuki coupling of commercially available 2,4-dichloropyrimidine 13
and boronic acid 14 affording the corresponding biaryl alcohol 15 which was then
subjected to the reaction with allyl bromide in the presence of tetrabutylammonium
hydrogensulfate (TBAHSO
) to give the diether 16.
4
19
According to this synthetic route, fragment 16
The second fragment 21 was synthesized starts with the nucleophilic attack of 2hydroxy-5-nitrobenzaldehyde 17 to 1-bromo-2-chloroethane in the presence of potassium
carbonate to afford the aromatic ether 18. The reduction of the aldehydic group of
compound 18 afforded the benzylic alcohol 19 which was then subjected to the reaction
with allyl bromide in the presence of tetrabutylammonium hydrogen sulfate (TBAHSO
to give the diether 20. The nitro group of diether 20 was reduced to amine under
iron/ammonium chloride conditions to produce the amine 21.
)
4
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Chemistry and Pharmacology of Drug Discovery
After the nucleophilic aromatic substitution of compound 21 with compound 16
to get compound 22, the ring-closing metathesis (RCM) afforded the macrocycle 23 via
ruthenium-based approach using the Zhan catalyst 1B. The macrocycle 23 was obtained
as inseparable mixtures of approximately 85:15 E/Z geometry. Compound 24 was finally
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Chapter 8. Pacritinib (Vonjo)
obtained via nucleophilic addition of pyrrolidine to the chloride of macrocycle 23 in
excellent yield and used directly for biological study as reported in the journal of
medicinal chemistry.
19
In 2018, a patent25 claimed a method of separating the isomers
applying an ion exchange medium comprising silver ions to give pure pacritinib (1).
Later in 2017, the selectivity of the RCM of diene 22 was further improved by
26
Shen et al.
using their molybdenum monoaryloxide pyrrolide complex catalyst (Mo-1).
They initially examined the RCM of boryl-diene 25. Subjection of 25 to 10 mol% Mo-1
at ambient temperature for 12 h resulted in an inefficient reaction (25% conversion; 17%
product 26) with higher E selectivity (93/7 E/Z). When the same reaction was performed
with an equivalent of B(C
isolated in 60% yield and 95/5 E/Z selectivity.
to avoid catalyst deactivation, product 26 could be
6F5)3
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Chemistry and Pharmacology of Drug Discovery
The same procedure with triether 27 is highly stereoselective, but the yield is
lower (34%). Triether 27 contains an additional di-ether fragment that might coordinate
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to the Lewis acidic molybdenum center to cause reduced catalyst activity; this was a
concern because the basicity of the new ether oxygen might be enhanced by the para
amino group. Therefore, they investigated the Boc-protected variant 28 assuming that this
modification would more firmly diminish the Lewis basicity of the pyrimidine and the
bis(ether) moiety. Thus subjecting 28 to the same reaction conditions but without
B(C
yield of 73% and 92/8 E/Z selectivity.
, and then removing the protecting group, resulted in product 23 at an overall
6F5)3
Chapter 8. Pacritinib (Vonjo)
7 Summary
Though the phase III studies of pacritinib (1) were placed on hold by the FDA in
February 2016 due to concerns over interim survival results, bleeding, and cardiovascular
events. Its developers did not lost courage and came with more detailed and
comprehensive data to satisfy FDA to remove the hold on its clinical trial and then
pacritinib (1) received its first accelerated conditional approval on February 28, 2022, in
the United States for the treatment of thrombocythemia and myelofibrosis. This
accelerated approval of pacritinib (1) will facilitate robust collection of real-world data
that would further help to understand the fullest extent of efficacy and safety of pacritinib
(1) in patients with myelofibrosis and severe thrombocytopenia. In patients with
myelofibrosis and thrombocytopenia, including those with prior anti-JAK therapy,
pacritinib (1) twice daily is more effective than BAT, including ruxolitinib (2), for
reducing splenomegaly and symptoms.
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Chapter 8. Pacritinib (Vonjo)
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____________________________________________________________
Tucatinib (Tukysa): An Oral, Selective HER2
Inhibitor for the Treatment of HER2-Positive
Solid Tumors
Fengtao Zhou and
Ke Ding
Tucatinib (1, Tukysa, ONT-380) was an oral highly selective human epidermal growthfactor receptor-2 (HER-2) tyrosine kinase inhibitor, developed by Seattle Genetics
(SeaGen). Tucatinib (1) was approved in April 2020 for the treatment of unresectable or
metastatic HER2-positive breast cancer in combination with trastuzumab and
capecitabine.
Before the approval of tucatinib (1), the dual tyrosine kinase inhibitors lapatinib
(2) and covalent inhibitor neratinib (3) have been clinically used to treat patients with
HER2-positive metastatic breast cancer (Figure
neratinib (3) displayed off-target adverse effects, including diarrhea and skin rashes, due
to the no selective blockage of both HER2 and EGFR. Tucatinib (1) is the first highly
selective HER2 inhibitor with approximately 500-fold more potent activities against
HER2 than EGFR, which exhibits fewer side effects resulting from the inhibition of
1
EGFR.
HER-2 positive breast cancer harboring brain metastases since it could cross the blood-
Furthermore, tucatinib (1) displays great potential to be used for the treatment of
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). However, both lapatinib (2) and
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