Abstract:Intervention of cancer cell mitosis by antitubulin drugs is among the most effective cancer chemotherapies. However, antitubulin drugs have dose-limiting side effects due to important functions of microtubules in resting normal cells and are often rendered ineffective by rapid emergence of resistance. Antimitotic agents with different mechanisms of action and improved safety profiles are needed as new treatment options. Mitosis-specific kinesin Eg5 represents an attractive anticancer target for discovering suc… Show more
“…Although (R)-K858 is a relatively non-sophisticated Eg5 inhibitor, compared to (S)-ARRY-520 (inhibition of the MT-stimulated Eg5 ATPase activity: IC 50 = 6 nM,[30]) and (R)-Litronesib (inhibition of the MT-stimulated Eg5 ATPase activity: IC 50 = 26 nM[31]), it nevertheless displays a complex network of interactions with residues in the inhibitor-binding pocket (Figure 3D). There are a variety of structural water molecules establishing interactions with (R)-K858, in particular the nitrogen atoms of the 1,3,4thiadiazole moiety and the N-acetamido group.…”
The thiadiazole scaffold is an important core moiety in a variety of clinical drug candidates targeting a range of diseases. For example, the 2,4,5-substituted 1,3,4-thiadiazole scaffold is present in a lead compound and at least two clinical candidates targeting the human motor protein Eg5, against neoplastic diseases. An inhibitor named K858 has in vivo activity in various mouse xenografts whereas the clinical candidates (S)-ARRY-520 and (R)-Litronesib have entered clinical trials with the former one in phase III clinical trials either alone or in combination with a proteasome inhibitor against relapsed/refractory multiple myeloma. Astonishingly, structural data are lacking for all thiadiazole-containing Eg5 inhibitors. Here we report the structure determination of two crystal forms of the ternary Eg5-ADP-K858 complex, locking the motor in the so-called final inhibitor bound state, thus blocking ADP release, a crucial stage for Eg5 activity. K858 acts at the established allosteric inhibitor-binding pocket formed of helix α2, loop L5 and helix α3. The structure of the complex has far reaching consequences for thiadiazole containing Eg5 inhibitors. For example, we could rationalise the structure-activity relationship in the crucial 5-position of the thiadiazole scaffold and the complex will serve in the future as a basis for strucutre-based drug design.
“…Although (R)-K858 is a relatively non-sophisticated Eg5 inhibitor, compared to (S)-ARRY-520 (inhibition of the MT-stimulated Eg5 ATPase activity: IC 50 = 6 nM,[30]) and (R)-Litronesib (inhibition of the MT-stimulated Eg5 ATPase activity: IC 50 = 26 nM[31]), it nevertheless displays a complex network of interactions with residues in the inhibitor-binding pocket (Figure 3D). There are a variety of structural water molecules establishing interactions with (R)-K858, in particular the nitrogen atoms of the 1,3,4thiadiazole moiety and the N-acetamido group.…”
The thiadiazole scaffold is an important core moiety in a variety of clinical drug candidates targeting a range of diseases. For example, the 2,4,5-substituted 1,3,4-thiadiazole scaffold is present in a lead compound and at least two clinical candidates targeting the human motor protein Eg5, against neoplastic diseases. An inhibitor named K858 has in vivo activity in various mouse xenografts whereas the clinical candidates (S)-ARRY-520 and (R)-Litronesib have entered clinical trials with the former one in phase III clinical trials either alone or in combination with a proteasome inhibitor against relapsed/refractory multiple myeloma. Astonishingly, structural data are lacking for all thiadiazole-containing Eg5 inhibitors. Here we report the structure determination of two crystal forms of the ternary Eg5-ADP-K858 complex, locking the motor in the so-called final inhibitor bound state, thus blocking ADP release, a crucial stage for Eg5 activity. K858 acts at the established allosteric inhibitor-binding pocket formed of helix α2, loop L5 and helix α3. The structure of the complex has far reaching consequences for thiadiazole containing Eg5 inhibitors. For example, we could rationalise the structure-activity relationship in the crucial 5-position of the thiadiazole scaffold and the complex will serve in the future as a basis for strucutre-based drug design.
“…Litronesib, developed by Kyowa Kirin and Eli Lilly and Company, was demonstrated to inhibit Eg-5 with an IC 50 of 26 nM in vitro [ 210 ]. At least seven phase I/II trials were completed, involving solid tumor patients treated with Litronesib as monotherapy or with G-CSF support (Pegfilgrastim and Filgrastim).…”
Mitosis represents a promising target to block cancer cell proliferation. Classical antimitotics, mainly microtubule-targeting agents (MTAs), such as taxanes and vinca alkaloids, are amongst the most successful anticancer drugs. By disrupting microtubules, they activate the spindle assembly checkpoint (SAC), which induces a prolonged delay in mitosis, expected to induce cell death. However, resistance, toxicity, and slippage limit the MTA’s effectiveness. With the desire to overcome some of the MTA’s limitations, mitotic and SAC components have attracted great interest as promising microtubule-independent targets, leading to the so-called second-generation antimitotics (SGAs). The identification of inhibitors against most of these targets, and the promising outcomes achieved in preclinical assays, has sparked the interest of academia and industry. Many of these inhibitors have entered clinical trials; however, they exhibited limited efficacy as monotherapy, and failed to go beyond phase II trials. Combination therapies are emerging as promising strategies to give a second chance to these SGAs. Here, an updated view of the SGAs that reached clinical trials is here provided, together with future research directions, focusing on inhibitors that target the SAC components.
“…Treatment with this compound resulted in a dose-dependent mitotic arrest of HCT-116 cells and subsequent cell death. Furthermore, LY2523355 showed marked antitumor activity in most of the xenograft tumor models, including patient-derived xenografts [ 74 ]. Fig.…”
In spite of substantial progress made toward understanding cancer pathogenesis, this disease remains one of the leading causes of mortality. Thus, there is an urgent need to develop novel, more effective anticancer therapeutics. Thiadiazole ring is a versatile scaffold widely studied in medicinal chemistry. Mesoionic character of this ring allows thiadiazole-containing compounds to cross cellular membrane and interact strongly with biological targets. Consequently, these compounds exert a broad spectrum of biological activities. This review presents the current state of knowledge on thiadiazole derivatives that demonstrate in vitro and/or in vivo efficacy across the cancer models with an emphasis on targets of action. The influence of the substituent on the compounds’ activity is depicted. Furthermore, the results from clinical trials assessing thiadiazole-containing drugs in cancer patients are summarized.
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