Kinsie E. Arnst
University of Tennessee Health Science Center
CancerMultiple drug resistanceChemistryApoptosisIn vitroMicrotubuleIn vivoColchicinePaclitaxelMelanomaMetastasisDrugCell cycleCancer researchMedicineCell cultureTubulinBiologyMitosisPharmacology
12Publications
7H-index
231Citations
Publications 13
Newest
#1Souvik Banerjee (University of Arkansas – Fort Smith)H-Index: 11
#2Foyez Mahmud (UTHSC: University of Tennessee Health Science Center)H-Index: 1
Last. Zhongzhi Wu (UTHSC: University of Tennessee Health Science Center)H-Index: 4
view all 17 authors...
Small molecules that interact with the colchicine binding site in tubulin have demonstrated therapeutic efficacy in treating cancers. We report the design, syntheses, and antitumor efficacies of new analogues of pyridopyrimidine and hydroquinoxalinone compounds with improved drug-like characteristics. Eight analogues, 5j, 5k, 5l, 5m, 5n, 5r, 5t, and 5u, showed significant improvement in metabolic stability and demonstrated strong antiproliferative potency in a panel of human cancer cell lines, i...
Source
#1Hongmei Cui (UTHSC: University of Tennessee Health Science Center)H-Index: 5
#2Kinsie E. Arnst (UTHSC: University of Tennessee Health Science Center)H-Index: 7
view all 4 authors...
Paclitaxel (PTX) is a first-line drug for late-stage non-small cell lung cancer (NSCLC) patients who do not benefit from targeted therapy or immunotherapy. However, patients invariably develop resistance to PTX upon prolonged treatments. Although diverse mechanisms leading to PTX resistance have been well-documented in the literature, strategies to overcome PTX resistance in NSCLC based on these mechanisms are still challenging. In this article, we reviewed recent advancements elucidating major ...
5 CitationsSource
#1Tao Wang (Zunyi Medical College)H-Index: 1
#2Chengyong Wu (Sichuan University)H-Index: 7
Last. Weimin Li (Sichuan University)H-Index: 24
view all 10 authors...
Abstract Microtubules are made up of tubulin protein and play a very important part in numerous cellular events of eukaryotic cells, which is why they are seen as attractive targets for tumor chemotherapy. BNC105, a known vascular targeting agent, has entered in phase II clinical trials. It has previously been confirmed that BNC105 is an effective microtubule targeting agent for various cancers. BNC105 exhibits selectivity for tumor cells, elicits vascular disrupting effects, and inhibits tumor ...
3 CitationsSource
#5Yong Li (St. Jude Children's Research Hospital)H-Index: 7
Because of its multifaceted role in cellular functions, tubulin is a validated and productive drug target for cancer therapy. While many tubulin inhibitors demonstrate clinical efficacy, they are often limited by the development of multidrug resistance. Therefore, implementation of tubulin inhibitors that can overcome resistance could provide significant therapeutic benefits. To optimize our previously reported tubulin inhibitor, 4a, we designed and synthesized two new analogues, SB202 and SB204...
5 CitationsSource
Interfering with microtubule dynamics is a well-established strategy in cancer treatment; however, many microtubule-targeting agents are associated with drug resistance and adverse effects. Substantial evidence points to ATP-binding cassette (ABC) transporters as critical players in the development of resistance. Herein, we demonstrate the efficacy of DJ95 (2-(1H-indol-6-yl)-4-(3,4,5-trimethoxyphenyl)-1H-imidazo[4,5-c]pyridine), a novel tubulin inhibitor, in a variety of cancer cell lines, inclu...
11 CitationsSource
#1Qinghui Wang (UTHSC: University of Tennessee Health Science Center)H-Index: 9
#2Kinsie E. Arnst (UTHSC: University of Tennessee Health Science Center)H-Index: 7
Last. Wei Li (Sichuan University)H-Index: 54
view all 8 authors...
ABI-231 is a potent, orally bioavailable tubulin inhibitor that interacts with the colchicine binding site and is currently undergoing clinical trials for prostate cancer. Guided by the crystal structure of ABI-231 in complex with tubulin, we performed structure–activity relationship studies around the 3-indole moiety that led to the discovery of several potent ABI-231 analogues, most notably 10ab and 10bb. The crystal structures of 10ab and 10bb in complex with tubulin confirmed their improved ...
13 CitationsSource
#1Kinsie E. Arnst (UTHSC: University of Tennessee Health Science Center)H-Index: 7
#2Souvik Banerjee (UTHSC: University of Tennessee Health Science Center)H-Index: 11
Last. Miller Duane D (UTHSC: University of Tennessee Health Science Center)H-Index: 6
view all 7 authors...
: Microtubule (MT)-targeting agents are highly successful drugs as chemotherapeutic agents, and this is attributed to their ability to target MT dynamics and interfere with critical cellular functions, including, mitosis, cell signaling, intracellular trafficking, and angiogenesis. Because MT dynamics vary in the different stages of the cell cycle, these drugs tend to be the most effective against mitotic cells. While this class of drug has proven to be effective against many cancer types, signi...
36 CitationsSource
#1Qinghui Wang (UTHSC: University of Tennessee Health Science Center)H-Index: 9
#2Kinsie E. Arnst (UTHSC: University of Tennessee Health Science Center)H-Index: 7
Last. Wei Li (Guangzhou Medical University)H-Index: 54
view all 11 authors...
Colchicine binding site inhibitors (CBSIs) hold great potential in developing new generations of antimitotic drugs. Unlike existing tubulin inhibitors such as paclitaxel, they are generally much less susceptible to resistance caused by the overexpression of drug efflux pumps. The 3,4,5-trimethoxyphenyl (TMP) moiety is a critical component present in many CBSIs, playing an important role in maintaining suitable molecular conformations of CBSIs and contributing to their high binding affinities to ...
24 CitationsSource
#1Qinghui Wang (UTHSC: University of Tennessee Health Science Center)H-Index: 9
#2Kinsie E. Arnst (UTHSC: University of Tennessee Health Science Center)H-Index: 7
Last. Wei Li (UTHSC: University of Tennessee Health Science Center)H-Index: 54
view all 8 authors...
Abstract The anti-apoptotic protein survivin is highly expressed in cancer cells but has a very low expression in fully differentiated adult cells. Overexpression of survivin is positively correlated with cancer cell resistance to chemotherapy and radiotherapy, cancer cell metastasis, and poor patient prognosis. Therefore, selective targeting survivin represents an attractive strategy for the development of anticancer therapeutics. Herein, we reported the extensive structural modification of our...
8 CitationsSource
#1Souvik Banerjee (UTHSC: University of Tennessee Health Science Center)H-Index: 11
#2Kinsie E. Arnst (UTHSC: University of Tennessee Health Science Center)H-Index: 7
Last. Duane D. Miller (UTHSC: University of Tennessee Health Science Center)H-Index: 65
view all 11 authors...
We report the design, synthesis, and biological evaluation of heterocyclic-fused pyrimidines as tubulin polymerization inhibitors targeting the colchicine binding site with significantly improved therapeutic index. Additionally, for the first time, we report high-resolution X-ray crystal structures for the best compounds in this scaffold, 4a, 4b, 6a, and 8b. These structures not only confirm their direct binding to the colchicine site in tubulin and reveal their detailed molecular interactions b...
52 CitationsSource