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FLT3: A Receptor Tyrosine Kinase Target in Adult and Pediatric AML
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Mark Levis, Patrick Brown, Donald Small
This indolocarbazole derivative was initially introduced as an inhibitor of Trkα for possible use in prostate cancer (153) but was recognized subsequently as a potent FLT3 inhibitor (120). A clinical-laboratory correlative phase 1 or 2 trial in relapsed or refractory AML patients with FLT3 mutations was initiated (175). The correlative assays from this trial revealed that if a patient had leukemic blasts that died when exposed to CEP-701 in vitro, and if that patient achieved a level of CEP-701 in plasma sufficient to significantly inhibit FLT3 autophosphorylation in a sustained fashion, then a clinical response was observed. Five out of fourteen patients showed a response, typically with reductions in peripheral blasts. One patient achieved a decrease in marrow blasts to less than 5% that persisted for three months. An additional phase 2 study of CEP-701 was conducted in the United Kingdom, in which elderly AML patients deemed not fit for standard therapy were treated with CEP-701 as a single agent (176). Clinical activity, manifest as transient reductions in bone marrow and peripheral blood blasts or longer periods of transfusion independence, was seen in three of five cases with mutated FLT3 and 5 of 22 wild-type FLT3 patients. Correlative data demonstrated that clinical responses occurred where the presence of sustained FLT3-inhibitory drug levels were combined with in vitro cytotoxic sensitivity of blasts to lestaurtinib.
Halogenases with Potential Applications for the Synthesis of Halogenated Pharmaceuticals
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Georgette Rebollar-Pérez, Cynthia Romero-Guido, Antonino Baez, Eduardo Torres
From the knowledge of indolocarbazole biosynthesis pathway, Sánchez et al. (2005) improved a combinatorial biosynthesis of novel antitumor indolocarbazole derivatives with chlorine atoms at new positions (Fig. 3.2). L. aerocolonigenes indolocarbazole core formation and modification genes were cloned in an operon-like fashion. Operons consisted of combinations of the L. aerocolonigenes reb genes with FAD-monooxygenase (staC) or P450 oxygenase (staP) genes from Streptomyces longisporoflavus, tryptophan 6-halogenase (thaI) gene from Streptomyces albogriseolus or tryptophan 5-halogenase (pyrH) gene from Streptomyces rugosporus. The resulting constructions expressed in S. albus J1074 produced indolocarbazole derivatives with chlorine atoms at novel positions. The cytotoxicity of representative products was tested against 14 tumor cell lines corresponding to nine cancer types (prostate, ovarian, breast, melanoma, non-small cell lung, leukemia, pancreas, colon and cervix). GI50 levels show that rebeccamycin and dideschlororebeccamycin were more potent than arcyriaflavin, K252c, 1-chloroacylriaflavin, chromopyrrolic acid and 1-chlorochromopyrrolic acid (compounds 12, 6, 2, 3, 9, 1 and 7 in Fig. 16.3.) but in lower levels than the control staurosporine. Rebeccamycin is chlorinated while dideschlororebeccamycin is not; nevertheless, both are glycosylated contrary to the rest of the derivatives (some of them chlorinated). These results agree with previous observations on the importance of carbohydrate residue more than chloride for Topoisomerase I inhibition (Prudhomme, 2000). Biosynthetic pathway for indolocarbazole derivatives.Adapted from Sánchez et al. (2005) with permission. Copyright (2005) National Academy of Sciences, U.S.A.
Design and biological evaluation of substituted 5,7-dihydro-6H-indolo[2,3-c]quinolin-6-one as novel selective Haspin inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Sreenivas Avula, Xudan Peng, Xingfen Lang, Micky Tortorella, Béatrice Josselin, Stéphane Bach, Stephane Bourg, Pascal Bonnet, Frédéric Buron, Sandrine Ruchaud, Sylvain Routier, Cleopatra Neagoie
For these reasons, some marine products and their synthetic analogues have emerged in drug discovery strategies and several of them have been reported for protein kinase inhibition2. Among them the most successful example is the polycyclic staurosporine I3,4. This lead compound has led from extraction, hemisynthesis and organic synthesis efforts to Lestaurtinib II5,6 and simplified Enzastaurin III7, two potent drugs targeting VEGF receptors and kinases, which have entered clinical trials against leukaemia and cancer (Figure 1). In this field, the chemical simplification of indolocarbazole scaffolds and caulersin IV have generated strong kinase inhibitors and cytotoxic agents8–14.
The effect of Gö6976 on chronic myeloid leukemia in vitro and in vivo
Published in Hematology, 2021
Zhen-Rui Cao, Xiao-Peng Chen, Min Feng, Yun-Long Hou, Yan Li, Xiao-Lei Hu, Zheng-Lan Huang, Jing Hu
CML is a malignant tumor that threatens human life, and the BCR/ABL1 fusion gene is an important factor in the development and deterioration of CML [13]. Recently, increasing evidence has shown that TKIs, a common anti-CML medicine, have little effect on ‘dormant’ CML stem cells [14]. However, ‘dormant’ CML stem cells are the key cause of CML recurrence and refractoriness. Therefore, it is important to find a new anti-CML medicine. As a type of indolocarbazole, Gö6976 can effectively inhibit the activity of PKC, thereby exerting anti-inflammatory, anti-immune and antitumor effects [15]. Gö6976 can inhibit tumor cell proliferation, slow tumor angiogenesis, and prevent tumor metastasis [16,17]. Gö6976 can act on many diseases, such as collagen-induced arthritis, melanoma, nasopharyngeal carcinoma and lung cancer [7–10]. However, the role of Gö6976 in CML remains unknown, and the toxicity of Gö6976 in mice has not yet been reported. Therefore, we explored the role of Gö6976 in CML and the toxic effects of Gö6976 in in vivo and in vitro experiments.
Opportunistic free-living amoebal pathogens
Published in Pathogens and Global Health, 2022
Mohammad Ridwane Mungroo, Naveed Ahmed Khan, Sutherland Maciver, Ruqaiyyah Siddiqui
Amphotericin B, one of the primary drugs of choice in the treatment of PAM, has been associated with multiple side effects, including use-limiting renal toxicity [156]. Hence, development of treatments against N. fowleri is still ongoing and in this effort, several compounds have been investigated against the amoeba in vitro. Azole agents, such as voriconazole, itraconazole, clotrimazole and ketoconazole, are antifungal agents that are effective against N. fowleri and ketoconazole was reported to be as effective as amphotericin B against N. fowleri [157,158]. Chlorpromazine and rokitamycin were revealed to be active against N. fowleri, both in vitro and in vivo, since at 12.5 μg/mL and 6.25 μg/mL, respectively, they completely inhibited the growth of the parasite [157]. Corifungin gave rise to 100% survival rate in mouse models infected with N. fowleri, indicating its efficacy against the parasite, which is thought to be related to affecting the mitochondria [159]. Tritrpticin showed antiamoebic activities at 100 μg/mL [158]., while secondary metabolites of Larrea tridentata were also shown to be effective against N. fowleri [160]. Diamidines, having the capability to cross the BBB, were shown to possess antiamoebic activities against N. fowleri [161] and ebselen compounds, which can also cross the BBB, were shown to possess antiamoebic activities against N. fowleri [162]. Recently, HMG-CoA reductase inhibitors were revealed as drug leads against N. fowleri, since pitavastatin, an inhibitor of HMG Co-A reductase, was able to kill 80% of trophozoites within 16hrs [163] and farnesyltransferase inhibitor lonafarnib showed activity against N. fowleri with EC50 of 1.5 µM [164]. Also, fluvastatin and atorvastatin were shown to cause programmed cell death in N. fowleri by analyzing cell membrane damage, condensed chromatin, ROS generation and mitochondrial membrane potential [165]. Moreover, staurosporine, an indolocarbazole from Streptomyces sanyensis, was shown to induce programmed cell death in N. fowleri with a low IC50 of 0.08 µM [166]. Anisomycin, prodigiosin and obatoclax are also compounds that have been shown to possess activity against N. fowleri at low micromolar concentrations [167]. Importantly, the antiparasitic agent, miltefosine, has been shown to be effective in the successful treatment and it has been recommended by the Centers for Disease Control and Prevention against PAM [168].