SCS LaureateS and awardS & FaLL Meeting 2019
CHIMIA 2019, 73, No. 7/8 569
26 is approximately 10- to 20-fold less active.[44] With regard to
other targets, midostaurin, 24 and 26 all potently inhibited both
the 3-phosphoinositide-dependent protein kinase 1 (PDPK1) and
vascular endothelial growth factor receptor kinase (VEGFR-2)
with IC50 values < 100 nM. Notably in non-small cell lung cancer
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[5] S. Schadt, B. Bister, S. K. Chowdhury, C. Funk, C. E. Hop, W. G. Humphreys,
Based upon the findings discussed above, attempts to antici-
pate or correlate the pharmacological properties and pharmacoki-
netic profile of midostaurin alone with the effects observed in
patients are unlikely to be of value, and contributions from the
metabolites 24 and 26 need to be taken into consideration.
F. Igarashi, A. D. James, M. Kagan, S. C. Khojasteh, A. N. Nedderman, C.
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into the Era of Genomically Targeted Cancer Drugs: 50 years of Anticancer
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5. Summary
Wartmann, M. Wiesmann, R. Woodman, N. Gallagher, Bioorg. Med. Chem.
The studies described in this article address the effects of me-
Lett. 2010, 18, 6977.
tabolites of three drugs used to treat leukaemia on their respective
[8] P. W. Manley, N. J. Stiefl, ‘Progress in the Discovery of BCR-ABL
oncoprotein targets in cells. If drug metabolites achieve adequate
levels in the circulation their effects are likely to translate into ef-
fects in patients. For example, imatinib is extensively demethylat-
ed in some CML patients to the less active, circulating metabolite
7, so that high rates of demethylation might be responsible for in-
ferior responses. In contrast, the second generation drug nilotinib
is not subject to extensive metabolism. In the case of midostaurin,
two major metabolites accumulate over time and the activity of
these might underlie at least some of the efficacy manifested in
AML patients: this also illustrates a limitation of single-dose drug
metabolism studies which do not detect metabolite accumulation.
Kinase Inhibitors for the Treatment of Leukemia’ in ‘Topics in Medicinal
Chemistry’, Ed. M. J. Waring, Springer International Publishing AG,
2017.
[9] T. Schindler, W. Bornmann, P. Pellicena, W. T. Miller, B. Clarkson, J.
[10] B. Nagar, W. G. Bornmann, P. Pellicena, T. Schindler, D. R. Veach, W. T.
[11] S. W. Cowan-Jacob, G. Fendrich, A. Floersheimer, P. Furet, J. Liebetanz,
G. Rummel, P. Rheinberger, M. Centeleghe, D. Fabbro, P. W. Manley, Acta
Cryst. 2007, 63, 80.
[12] N. Vajpai, A. Strauss, G. Fendrich, S. W. Cowan-Jacob, P. W. Manley, S.
[13] R. A. Larson, B. J. Druker, F. Guilhot, S. G. O’Brien, G. J. Riviere, T.
The efficacy of drugs is also related to the ability of the patient to
tolerate adverse events at the doses administered and, particularly
[15] N. Nebot, S. Crettol, F. d’Esposito, B. Tattam, D. E. Hibbs, M. Murray, Br.
because of polypharmacologies, metabolites might be associated
with more severe or different off-target effects than the parent
drug: this latter aspect is not addressed in the present study.
An understanding of the binding modes of drugs is useful for
predicting the activity of putative metabolites against the target
protein and, where metabolic deactivation is to be expected, strat-
egies can be considered to mitigate the formation of such me-
[16] H. Gschwind, U. Pfaar, F. Waldmeier, M. Zollinger, C. Sayer, P. Zbinden,
[17] M.p. 226–227 °C (EtOH). 1H-NMR (600 MHz, DMSO-d6): δ 10.20 (s, 1H),
9.27 (d, J = 2.3 Hz, 1H), 9.01 (s, 1H), 8.68 (dd, J = 4.7, 1.6 Hz, 1H), 8.55–
8.43 (m, 2H), 8.07 (d, J = 2.2 Hz, 1H), 7.91 (d, J = 7.9 Hz, 2H), 7.58–7.40
(m, 5H), 7.20 (d, J = 8.4 Hz, 1H), 3.61 (s, 2H), 3.03 (s, 3H), 2.83 (t, J = 11.2
Hz, 4H), 2.53 (s, 3H), 2.22 (s, 3H).
tabolites. Thus in the case of imatinib, in an attempt to reduce
[18] M.p. 242–244 °C (CH2Cl -MeOH). 1H-NMR (600 MHz, DMSO-d6): δ
10.25 (s, 1H), 9.28 (d, J = 22.2 Hz, 1H), 8.99 (s, 1H), 8.68 (dd, J = 4.8, 1.7
Hz, 1H), 8.51 (d, J = 5.1 Hz, 1H), 8.48 (dt, J = 8.0, 2.0 Hz, 1H), 8.08 (d, J =
2.2 Hz, 1H), 7.93 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 8.2 Hz, 2H), 7.52 (dd, J =
8.0, 4.8 Hz, 1H), 7.48 (dd, J = 8.2, 2.2 Hz, 1H), 7.43 (d, J = 5.1 Hz, 1H), 7.21
(d, J = 8.4 Hz, 1H), 4.48 (s, 2H), 4.12–3.94 (m, 4H), 3.10 (s, 3H), 2.85 (d, J
= 9.1 Hz, 2H), 2.72 (d, J = 8.9 Hz, 2H), 2.22 (s, 3H).
conversion to the N-desmethylpiperazine metabolite 7, both the
N-ethyl and N-deuteromethyl imatinib analogues were evaluat-
ed, although following the discovery of nilotinib neither of these
strategies were pursued.[22,50] Although neither 5 nor 15 were
major metabolites of imatinib or nilotinib, a potential strategy to
mitigate the oxidation of the phenyl-CH3 moieties would be to
replace the methyl group with a halogen atom. In the case of nilo-
tinib the 4-fluorobenzamide analogue (prepared by reacting 21
with 4-fluoro-3-nitrobenzoyl chloride, followed by elaboration in
a manner analogous to that in Scheme 4) was less active (32D cell
[19] K. O. Börnsen, P. End, G. Gross, U. Pfaar, P. W. Manley, J. Zimmermann,
US Patent Appl. No. US 2010/0222362, 2010.
[20] M.p. 254–255 °C (MeOH). 1H-NMR (600 MHz, DMSO-d6): δ 10.19 (s, 1H),
9.10 (s, 1H), 8.85 (s, 1H), 8.55 (d, J = 5.0 Hz, 1H), 8.33 (d, J = 6.4 Hz, 1H),
8.13–8.00 (m, 2H), 7.91 (d, J = 7.9 Hz, 2H), 7.59–7.47 (m, 2H), 7.44 (dd, J
= 9.4, 6.5 Hz, 3H), 7.21 (d, J = 8.2 Hz, 1H), 3.52 (s, 2H), 2.35 (s, 6H), 2.21
GI50 149 ± 17 nM). The activity observed for the aniline 18 against
BCR-ABL1 suggests that this compound exploits different bind-
ing interactions to those of nilotinib (18 is also more potent than
(s, 3H), 2.15 (s, 3H).
[21] J. Zimmermann, E. Buchdunger, H. Mett, T. Meyer, N. B. Lydon, P. Traxler,
[22] P. W. Manley, F. Blasco, J. Mestan, R. Aichholz, Bioorg. Med. Chem. 2013,
nilotinib against KIT autophosphorylation in the GIST882 gastro-
21, 3231.
intestinal stomal tumour cell line),[51] however exploiting this with
1
[23] M.p. > 140 °C (decomp.; MeOH). H-NMR (500 MHz, DMSO-d6): δ
a molecule designed to have the amine as an unmasked pharma-
cophore element would not be without liabilities.
In conclusion, studies such as these contribute to our under-
standing of the potential roles of metabolites in drug efficacy and
can provide useful information for preclinical drug discovery ac-
tivities to find new therapeutics.
10.18 (s, 1H), 9.26 (d, J = 1.98 Hz, 1H), 8.99 (s, 1H), 8.67 (dd, J = 4.73,
1.53 Hz, 1H), 8.50 (d, J = 5.04 Hz, 1H), 8.47 (m. 1H), 8.06 (s, 1H), 7.91
(d, J = 8.09, 1H), 7.51 (dd, J = 7.93, 4.73 Hz, 1H), 7.46 (m, 3H), 7.42
(d, J = 5.19 Hz, 1H), 7.19 (d, J = 8.39 Hz, 1H), 3.60 (s, 2H), 3.26 (t, J =
5.42 Hz, 2H), 2.96 (s, 2H), 2.80 (s, 3H), 2.63 (t, J = 5.49 Hz, 2H), 2.21
(s, 3H).
1
[24] M.p. 196–198 °C (MeOH-EtOAc). H-NMR (500 MHz, DMSO-d6) δ 2.14
(s, 3H), 2.25–2.45 (m, 8H), 3.52 (s, 2H), 4.56 (s, 2H), 5.50 (brs, 1H), 7.29
(d, J = 8.3 Hz, 1H), 7.41 (dd, J = 2.0, 8.3 Hz, 1H), 7.44 (d, J = 8.1 Hz, 2H),
7.50 (d, J = 5.1 Hz, 1H), 7.52 (dd, J = 3.3, 8.1 Hz, 1H), 7.93 (d, J = 8.1 Hz,
2H), 8.56 (d, J = 2.0 Hz, 1H), 8.57 (d, J = 5.1 Hz, 1H), 8.59 (ddd, J = 1. 4,
2.1, 8.1 Hz, 1H), 8.69 (dd, J = 1.4, 3.3 Hz, 1H), 9.10 (s, 1H), 9.33 (d, J = 2.1
Hz, 1H) and 10.22 (s, 1H).
Acknowledgements
I wish to acknowledge the mentoring and encouragement provided
by Professors Alex Matter (Novartis Pharma AG) and James D. Griffin
(Dana-Farber Cancer Institute, Boston, MS). Markus Gaugler is thanked
for his skilled practical work in preparing authentic samples of metabo-
lites, together with Dr. Jürgen Mestan and his team for measuring their
effects on cellular BCR-ABL1 kinase activity.
[26] M. J. Eck, P. W. Manley, Current Opin. Cell Biol. 2009, 21, 288.
Received: May 10, 2019