ABL kinase inhibitory and antiproliferative activity of novel picolinamide based benzothiazoles

El-Damasy, Ashraf K.; Cho, Nam-Chul; Kang, Seonmi; Pae, Ae Nim; Keum, Gyochang

doi:10.1016/j.bmcl.2015.03.067

Cited by 21 publications

(9 citation statements)

References 28 publications

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“…This cyclohexanol is theorized to play a critical role in its CSF-1 receptor inhibition for competitively binding to the receptor ATP binding site to block phosphorylation, and its modification has been shown to significantly reduce its inhibitory potency. 14,33 Therefore, by blocking the cyclohexanol group via conjugation of the hydroxyl group to succinic anhydride (2), we expect that BLZ will remain inactive while conjugated to the dendrimer to mitigate potential systemic toxicities until the dendrimer reaches TAMs for release. Triggered pH sensitive release was confirmed, with more rapid BLZ release from the dendrimer in acidic conditions compared to neutral conditions.…”

Section: Discussionmentioning

confidence: 99%

Targeted systemic dendrimer delivery of CSF‐1R inhibitor to tumor‐associated macrophages improves outcomes in orthotopic glioblastoma

Liaw

Reddy

Sharma

et al. 2020

Bioengineering & Transla Med

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Glioblastoma is the most common and aggressive form of primary brain cancer, with median survival of 16–20 months and a 5‐year survival rates of <5%. Recent advances in immunotherapies have shown that addressing the tumor immune profile by targeting the colony‐stimulating factor 1 (CSF‐1) signaling pathway of tumor‐associated macrophages (TAMs) has the potential to improve glioblastoma therapy. However, such therapies have shown limited successes in clinical translation partially due to lack of specific cell targeting in solid tumors and systemic toxicity. In this study, we present a novel hydroxyl dendrimer‐mediated immunotherapy to deliver CSF‐1R inhibitor BLZ945 (D‐BLZ) from systemic administration selectively to TAMs in glioblastoma brain tumors to repolarize the tumor immune environment in a localized manner. We show that conjugation of BLZ945 to dendrimers enables sustained release in intracellular and intratumor conditions. We demonstrate that a single systemic dose of D‐BLZ targeted to TAMs decreases pro‐tumor expression in TAMs and promotes cytotoxic T cell infiltration, resulting in prolonged survival and ameliorated disease burden compared to free BLZ945. Our results demonstrate that dendrimer‐drug conjugates can facilitate specific, localized manipulation of tumor immune responses from systemic administration by delivering immunotherapies selectively to TAMs, thereby improving therapeutic efficacy while reducing off‐target effects.

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Section: Discussionmentioning

confidence: 99%

Targeted systemic dendrimer delivery of CSF‐1R inhibitor to tumor‐associated macrophages improves outcomes in orthotopic glioblastoma

Liaw

Reddy

Sharma

et al. 2020

Bioengineering & Transla Med

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“…As illustrated in Scheme , in order to prepare the target compounds, we synthesized the two main building blocks 3 a , 3 b and 4 . The anilines 3 a and 3 b were prepared in three steps.…”

Section: Figurementioning

confidence: 99%

“…As illustrated in Scheme 1, in order to preparet he target compounds, we synthesized the two main buildingb locks 3a, 3b and 4. [17,18] The anilines 3a and 3b were prepared in three steps. First, a-bromination of 1-methyl-4-nitro-2-(trifluoromethyl)benzenew ith N-bromosuccinimide (NBS) in the presence of azobisisobutyronitrile( AIBN) afforded the corresponding bromo derivative 1 in 63 %y ield.…”

mentioning

confidence: 99%

“…[19] Nucleophilic substitution of 1 with morpholine or 4-ethylpiperazine using K 2 CO 3 as ab ase in dichloromethane produced the alkylated nitro derivatives 2a and 2b,w hichu nderwent reduction with Pd/C under hy-drogen atmosphere to yield the corresponding anilines 3a and 3b.O nt he other hand, the 2-aminobenzothiazole derivative 4 was prepared adoptingo ur previously reported method. [17,18] Treatmento ft he benzothiazol-2-yl amine 4 with 1,1'-carbonyldiimidazole (CDI) in DMF at room temperature produced the corresponding isocyanate.I nt he same pot, the appropriate aniline 3a or 3b was added and the reaction mixture was heated at 100 8Cf or 3hto afford the desired ureidobenzothiazoles 5 and 6.…”

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confidence: 99%

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Discovery of a Nanomolar Multikinase Inhibitor (KST016366): A New Benzothiazole Derivative with Remarkable Broad‐Spectrum Antiproliferative Activity

et al. 2016

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Herein we report the discovery of compound 6 [KST016366; 4-((2-(3-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)benzo[d]thiazol-6-yl)oxy)picolinamide] as a new potent multikinase inhibitor through minor structural modification of our previously reported RAF kinase inhibitor A. In vitro anticancer evaluation of 6 showed substantial broad-spectrum antiproliferative activity against 60 human cancer cell lines. In particular, it showed GI50 values of 51.4 and 19 nm against leukemia K-562 and colon carcinoma KM12 cell lines, respectively. Kinase screening of compound 6 revealed its nanomolar-level inhibitory activity of certain oncogenic kinases implicated in both tumorigenesis and angiogenesis. Interestingly, 6 displays IC50 values of 0.82, 3.81, and 53 nm toward Tie2, TrkA, and ABL-1 (wild-type and T315I mutant) kinases, respectively. Moreover, 6 is orally bioavailable with a favorable in vivo pharmacokinetic profile. Compound 6 may serve as a promising candidate for further development of potent anticancer chemotherapeutics.

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“…Chronic myelogenous leukemia (CML) is a malignant proliferative tumor originating from hematopoietic stem cells (Nash, 1999;Sinclair et al, 2013). More than 95% of CML patients have characteristic gene abnormalities, that is, the long-arm c-Abl proto-oncogene translocation of chromosome 9 to the breakpoint cluster region (Bcr) on the long arm of chromosome 22 to form Bcr-Abl fusion gene (El-Damasy et al, 2015;Munikrishnappa et al, 2016). Bcr-Abl fusion gene is transcribed and translated to produce the P210 protein.…”

Section: Introductionmentioning

confidence: 99%

Recent advances in Bcr‐Abl tyrosine kinase inhibitors for overriding T315I mutation

et al. 2020

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BCR-ABL is a gene produced by the fusion of the bcr gene and the c-abl protooncogene and is considered to be the main cause of chronic myelogenous leukemia (CML) production. Therefore, the development of selective Bcr-Abl kinase inhibitors is an attractive strategy for the treatment of CML. However, in the treatment of CML with a Bcr-Abl kinase inhibitor, the T315I gatekeeper mutant disrupts the important contact interaction between the inhibitor and the enzyme, resistant to the first-and second-generation drugs currently approved, such as imatinib, bosutinib, nilotinib, and dasatinib. In order to overcome this special resistance, several different strategies have been explored, and many molecules have been studied to effectively inhibit Bcr-Abl T315I. Some of these molecules are still under development, and some are being studied preclinically, and still others are in clinical research. Herein, this review reports some of the major examples of third-generation Bcr-Abl inhibitors against the T315I mutation.

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ABL kinase inhibitory and antiproliferative activity of novel picolinamide based benzothiazoles

Cited by 21 publications

References 28 publications

Targeted systemic dendrimer delivery of CSF‐1R inhibitor to tumor‐associated macrophages improves outcomes in orthotopic glioblastoma

Targeted systemic dendrimer delivery of CSF‐1R inhibitor to tumor‐associated macrophages improves outcomes in orthotopic glioblastoma

Discovery of a Nanomolar Multikinase Inhibitor (KST016366): A New Benzothiazole Derivative with Remarkable Broad‐Spectrum Antiproliferative Activity

Recent advances in Bcr‐Abl tyrosine kinase inhibitors for overriding T315I mutation

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