Design and synthesis of chloroquine analogs with anti-breast cancer property

Solomon, V. Raja; Hu, Changkun; Lee, Hoyun

doi:10.1016/j.ejmech.2010.05.046

Cited by 39 publications

(34 citation statements)

References 26 publications

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“…Studies that have investigated the use of CQ analogs in cancer treatment have primarily focused on their ability to induce cell death as single agents 60 . Even though cytotoxic compounds are valuable, potent autophagy inhibition alone does not necessarily elicit cytotoxic effects.…”

Section: Discussionmentioning

confidence: 99%

Development of potent autophagy inhibitors that sensitize oncogenic BRAF V600E mutant melanoma tumor cells to vemurafenib

Goodall

Wang²,

Martin

et al. 2014

Autophagy

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Autophagy is a dynamic cell survival mechanism by which a double-membrane vesicle, or autophagosome, sequesters portions of the cytosol for delivery to the lysosome for recycling. This process can be inhibited using the antimalarial agent chloroquine (CQ), which impairs lysosomal function and prevents autophagosome turnover. Despite its activity, CQ is a relatively inadequate inhibitor that requires high concentrations to disrupt autophagy, highlighting the need for improved small molecules. To address this, we screened a panel of antimalarial agents for autophagy inhibition and chemically synthesized a novel series of acridine and tetrahydroacridine derivatives. Structure-activity relationship studies of the acridine ring led to the discovery of VATG-027 as a potent autophagy inhibitor with a high cytotoxicity profile. In contrast, the tetrahydroacridine VATG-032 showed remarkably little cytotoxicity while still maintaining autophagy inhibition activity, suggesting that both compounds act as autophagy inhibitors with differential effects on cell viability. Further, knockdown of autophagy-related genes showed no effect on cell viability, demonstrating that the ability to inhibit autophagy is separate from the compound cytotoxicity profiles. Next, we determined that both inhibitors function through lysosomal deacidification mechanisms and ultimately disrupt autophagosome turnover. To evaluate the genetic context in which these lysosomotropic inhibitors may be effective, they were tested in patient-derived melanoma cell lines driven by oncogenic BRAF (v-raf murine sarcoma viral oncogene homolog B). We discovered that both inhibitors sensitized melanoma cells to the BRAF V600E inhibitor vemurafenib. Overall, these autophagy inhibitors provide a means to effectively block autophagy and have the potential to sensitize mutant BRAF melanomas to first-line therapies.

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Section: Discussionmentioning

confidence: 99%

Development of potent autophagy inhibitors that sensitize oncogenic BRAF V600E mutant melanoma tumor cells to vemurafenib

Goodall

Wang²,

Martin

et al. 2014

Autophagy

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“…Subsequently, a series of tetraquinolines was reported with potent antimalarial properties (13), confirming that polyvalency could afford increased potency. Augmented cytotoxicity was observed in cancer cell lines when Akt inhibitors were combined with fluorinated quinolines (16), and CQ analogs with a piperazine connector had enhanced anticancer properties compared with CQ (17). These results suggest that the CQ scaffold could serve as the basis for the development of effective cancer chemotherapeutics, but to date the properties of dimeric CQ derivatives as anticancer therapeutics have not been investigated.…”

mentioning

confidence: 86%

Autophagy inhibitor Lys05 has single-agent antitumor activity and reproduces the phenotype of a genetic autophagy deficiency

McAfee¹,

Zhang²,

Samanta³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

357

313

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Autophagy is a lysosome-dependent degradative process that protects cancer cells from multiple stresses. In preclinical models, autophagy inhibition with chloroquine (CQ) derivatives augments the efficacy of many anticancer therapies, but CQ has limited activity as a single agent. Clinical trials are underway combining anticancer agents with hydroxychloroquine (HCQ), but concentrations of HCQ required to inhibit autophagy are not consistently achievable in the clinic. We report the synthesis and characterization of bisaminoquinoline autophagy inhibitors that potently inhibit autophagy and impair tumor growth in vivo. The structural motifs that are necessary for improved autophagy inhibition compared with CQ include the presence of two aminoquinoline rings and a triamine linker and C-7 chlorine. The lead compound, Lys01, is a 10-fold more potent autophagy inhibitor than HCQ. Compared with HCQ, Lys05, a water-soluble salt of Lys01, more potently accumulates within and deacidifies the lysosome, resulting in impaired autophagy and tumor growth. At the highest dose administered, some mice develop Paneth cell dysfunction that resembles the intestinal phenotype of mice and humans with genetic defects in the autophagy gene ATG16L1, providing in vivo evidence that Lys05 targets autophagy. Unlike HCQ, significant single-agent antitumor activity is observed without toxicity in mice treated with lower doses of Lys05, establishing the therapeutic potential of this compound in cancer.cell death | stress responses | cancer cell survival | drug resistance | antimalarials A utophagy, the sequestration of organelles and proteins in autophagic vesicles (AVs) and degradation of this cargo through lysosomal fusion (1), allows tumor cells to survive metabolic and therapeutic stresses (2-5). Therapy-induced autophagy is a key resistance mechanism to many anticancer agents (6), and autophagy levels are increased in most cancers (7). Chloroquine (CQ; Fig. 1, compound 1) derivatives block autophagy by impairing lysosomal function (3,8,9). Studies in multiple mouse models of malignancy have demonstrated that autophagy inhibition with CQ derivatives augments the efficacy of a variety of anticancer agents. Clinical trials combining cancer therapies with hydroxychloroquine (HCQ; Fig. 1), have been launched, and preliminary results indicate these combinations have activity (6). However, pharmacokinetic (PK)-pharmacodynamic (PD) studies conducted in patients receiving HCQ for cancer therapy have indicated that the high micromolar concentrations of HCQ required to inhibit autophagy in vitro are inconsistently achieved in humans (10). There is an unmet need to develop more potent inhibitors of autophagy.The design and synthesis of dimeric analogs of CQ that exploit the thermodynamic advantages imparted by polyvalency (11, 12) has been previously studied in the context of malaria (13-15). The synthesis of heteroalkane-bridged bisquinolines did not produce sufficient antimalarial activity to warrant further investigation (14). Subsequently, a seri...

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“…We previously found that the antiproliferative effect of 4-piperazinylquinoline-isatin hybrid compounds is substantially more active for cancer than noncancer cells (23). Other groups showed that sulfonyl derivatives often possess effective antitumor activity (24).…”

Section: Introductionmentioning

confidence: 99%

VR23: A Quinoline–Sulfonyl Hybrid Proteasome Inhibitor That Selectively Kills Cancer via Cyclin E–Mediated Centrosome Amplification

Pundir

Vu²,

Solomon³

et al. 2015

Cancer Research

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The proteasome is clinically validated as a target for cancer therapeutics. However, proteasome-inhibitory agents that are cancer selective have yet to be developed. In this study, we report the identification of a safe and effective proteasome inhibitor with selective anticancer properties. We screened a chemical library constructed using a hybrid approach that incorporated a 4-piperazinylquinoline scaffold and a sulfonyl phamarcophore. From this library, we identified 7-chloro-4-(4-(2,4-dinitrophenylsulfonyl)piperazin-1-yl)quinoline (VR23) as a small molecule that potently inhibited the activities of trypsin-like proteasomes (IC 50 ¼ 1 nmol/L), chymotrypsin-like proteasomes (IC 50 ¼ 50-100 nmol/L), and caspase-like proteasomes (IC 50 ¼ 3 mmol/L). Data from molecular docking and substrate competition assays established that the primary molecular target of VR23 was b2 of the 20S proteasome catalytic subunit. Notably, VR23 was structurally distinct from other known proteasome inhibitors and selectively killed cancer cells by apoptosis, with little effect on noncancerous cells. Mechanistic investigations showed that cancer cells exposed to VR23 underwent an abnormal centrosome amplification cycle caused by the accumulation of ubiquitinated cyclin E. In combinations with the clinically approved chymotrypsin-like proteasome inhibitor bortezomib, VR23 produced a synergistic effect in killing multiple myeloma cells, including those that were resistant to bortezomib. VR23 was effective in vivo in controlling multiple myelomas and metastatic breast cancer cells, in the latter case also enhancing the antitumor activity of paclitaxel while reducing its side effects. Overall, our results identify VR23 as a structurally novel proteasome inhibitor with desirable properties as an anticancer agent. Cancer Res; 75(19); 4164-75. Ó2015 AACR.

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Design and synthesis of chloroquine analogs with anti-breast cancer property

Cited by 39 publications

References 26 publications

Development of potent autophagy inhibitors that sensitize oncogenic BRAF V600E mutant melanoma tumor cells to vemurafenib

Development of potent autophagy inhibitors that sensitize oncogenic BRAF V600E mutant melanoma tumor cells to vemurafenib

Autophagy inhibitor Lys05 has single-agent antitumor activity and reproduces the phenotype of a genetic autophagy deficiency

VR23: A Quinoline–Sulfonyl Hybrid Proteasome Inhibitor That Selectively Kills Cancer via Cyclin E–Mediated Centrosome Amplification

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