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Antitubulin Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
A number of Aurora Kinase inhibitors have been reported, and examples include VX-680 (Tozasertib), ZM447439 (a chemical probe), Hesperadin, TAK-901, and AZD-1152 (Figure 4.28). Tozasertib was in clinical development in a joint program between Vertex Pharmaceuticals and Merck & Co. It is a potent inhibitor of all aurora kinases, including types A, B, and C, and has been shown to inhibit cell-cycle progression, induce apoptosis, and block tumor growth in a number of in vivo xenograft models including those based on leukemias and colon and pancreatic tumors. However, a clinical trial was suspended in 2007 due to an observed QT-prolongation cardiotoxicity. Similarly, AstraZeneca developed AZD-1152 (also known as barasertib), although development was halted at the Phase II stage. These agents are all administered intravenously and share Grade-3 neutropenia as the most serious dose-limiting side effect. Structures of some known inhibitors of the Aurora kinases.
Tropomyosin receptor kinase inhibitors: an updated patent review for 2016–2019
Published in Expert Opinion on Therapeutic Patents, 2020
Justin J. Bailey, Carolin Jaworski, Donovan Tung, Carmen Wängler, Björn Wängler, Ralf Schirrmacher
BioMed X (Heidelberg, Germany) redesigned the Aurora kinase A (AurA) inhibitor tozasertib (formerly VX-680) as a TrkA inhibitor, based on its promiscuity with TrkA (IC50 = 2 nM) [54]. Tozasertib (Figure 4(a)) was systematically modified through an in silico-driven design effort to shift its inhibitor selectivity away from AurA. A small library of analogs was synthesized with functionalities extending toward the gatekeeper phenylalanine, F589, of TrkA. The cyclopropylcarboxamide moiety was removed to reduce potential steric clashes with these newly introduced groups (Figure 4(b)). The lead inhibitor a-1 (Figure 4(c)) exhibits over 10,000-fold improved selectivity for TrkA over AurA (TrkA Kd = 0.46, AurA Kd = 4450), effectively converting a drug originally developed to target AurA for cancer treatment, toward TrkA as a target for pain management. This work is detailed in patent WO2019101843 [55].
Flavin-containing monooxygenase 3 (FMO3): genetic variants and their consequences for drug metabolism and disease
Published in Xenobiotica, 2020
Ian R. Phillips, Elizabeth A. Shephard
A third variant, c.769G>A[p.(Val257Met)] (Treacy et al., 1998), is relatively common in Asians (∼13% allele frequency), but less so in Europeans (6–7%) and Africans (<4%). The variant significantly reduces the ability of the enzyme to catalyze N-oxygenation of the anticancer aurora kinase inhibitor danusertib, but has no effect on the N-oxygenation of another aurora kinase inhibitor, tozasertib (Catucci et al., 2013), or on the oxygenation of a range of other substrates (Cashman 2004; Cashman & Zhang, 2006; Dolphin et al., 2000; Koukouritaki & Hines, 2005; Krueger & Williams, 2005; Shimizu, et al., 2007b). The variant c.394G>C[p.(Asp132His)] (Furnes et al., 2003), which is present at a frequency of ∼4% in Africans, but is extremely rare in Europeans and Asians, moderately reduces activity towards trimethylamine and methimazole, but not 10-(N,N-dimethylaminopentyl)-2-(trifluoromethyl) phenothiazine (Lattard et al., 2003).
From bench to bedside: bridging the gaps in best practices for real-world chronic myeloid leukemia care
Published in Expert Review of Hematology, 2022
Giovanni Manfredi Assanto, Emilia Scalzulli, Ida Carmosino, Maurizio Martelli, Massimo Breccia
New molecules are currently being tested to further improve treatment strategies in CML. New generations TKI such as PF-114, HQP1351 (olverembatinib) and K0706 (vodobatinib) are employed in phase I clinical trials. PF-114 share the activity spectrum of ponatinib, differences in molecular structure aim to minimize cardiovascular side effects [55,76]. Olverembatinib instead is able to bind the ATP-binding pocket in presence of T315I mutation. Other inhibitors are being validated in preclinical models, such as bafetinib, tozasertib, or danusertib [71].