Discovery of selective, orally bioavailable inhibitor of mouse chitotriosidase

Mazur, Marzena; Bartoszewicz, Agnieszka; Dymek, Barbara; Salamon, Magdalena; Andryianau, Gleb; Kowalski, Michał; Olejniczak, Sylwia; Matyszewski, Krzysztof; Pluta, Elżbieta; Borek, Bartłomiej; Stefaniak, Filip; Zagożdżon, Agnieszka; Mazurkiewicz, Marcin; Koralewski, Robert; Czestkowski, Wojciech; Piotrowicz, Michał; Niedziejko, Piotr; Gruza, Mariusz; Dzwonek, Karolina; Gołębiowski, Adam; Gołąb, Jakub; Olczak, Jacek

doi:10.1016/j.bmcl.2017.12.047

Cited by 12 publications

(25 citation statements)

References 18 publications

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“…In this work, we have examined the effects of a novel class of 1-(substituted-sulfonyl)-2-aminoimidazoline derived, synthetic, small molecules [ 14 ] on a range of cancer cell lines in vitro, and in vivo, in two tumor xenograft mouse models. The chemical structure of these compounds provides easy water solubility, suggestive of the potential for enhanced bioavailability in vivo [ 15 , 16 ], and so represents a possible way to augment the current cancer treatment landscape. We found that OAT-449 (molecular weight 232 Da; for comparison, vincristine’s MW is 825 Da), one of these new, small, water-soluble 2-aminoimidazoline derivatives, is a potent inhibitor of tubulin polymerization, which at nanomolar concentrations induces mitotic catastrophe in colorectal adenocarcinoma HT-29 and cervical adenocarcinoma HeLa cells.…”

Section: Introductionmentioning

confidence: 99%

A New Inhibitor of Tubulin Polymerization Kills Multiple Cancer Cell Types and Reveals p21-Mediated Mechanism Determining Cell Death after Mitotic Catastrophe

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Mietelska‐Porowska

et al. 2020

Cancers

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Induction of mitotic catastrophe through the disruption of microtubules is an established target in cancer therapy. However, the molecular mechanisms determining the mitotic catastrophe and the following apoptotic or non-apoptotic cell death remain poorly understood. Moreover, many existing drugs targeting tubulin, such as vincristine, have reduced efficacy, resulting from poor solubility in physiological conditions. Here, we introduce a novel small molecule 2-aminoimidazoline derivative—OAT-449, a synthetic water-soluble tubulin inhibitor. OAT-449 in a concentration range from 6 to 30 nM causes cell death of eight different cancer cell lines in vitro, and significantly inhibits tumor development in such xenograft models as HT-29 (colorectal adenocarcinoma) and SK-N-MC (neuroepithelioma) in vivo. Mechanistic studies showed that OAT-449, like vincristine, inhibited tubulin polymerization and induced profound multi-nucleation and mitotic catastrophe in cancer cells. HeLa and HT-29 cells within 24 h of treatment arrested in G2/M cell cycle phase, presenting mitotic catastrophe features, and 24 h later died by non-apoptotic cell death. In HT-29 cells, both agents altered phosphorylation status of Cdk1 and of spindle assembly checkpoint proteins NuMa and Aurora B, while G2/M arrest and apoptosis blocking was consistent with p53-independent accumulation in the nucleus and largely in the cytoplasm of p21/waf1/cip1, a key determinant of cell fate programs. This is the first common mechanism for the two microtubule-dissociating agents, vincristine and OAT-449, determining the cell death pathway following mitotic catastrophe demonstrated in HT-29 cells.

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Section: Introductionmentioning

confidence: 99%

A New Inhibitor of Tubulin Polymerization Kills Multiple Cancer Cell Types and Reveals p21-Mediated Mechanism Determining Cell Death after Mitotic Catastrophe

Zdioruk

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Mietelska‐Porowska

et al. 2020

Cancers

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“…Other replacements of the oxygen atoms (compounds 5 – 8 ) proved to be inferior, with piperazine 6 being the most promising lead molecule. Further development of the SAR of compound 6 led to a higher mCHIT1 selectivity at the cost of activity against human enzymes, and although it gave an interesting tool molecule, i.e., mCHIT1 selective inhibitor OAT-2068 , it was later discontinued.…”

Section: Resultsmentioning

confidence: 99%

“…20 The initial SAR development led to improvement of in vitro activity by optimizing interactions with Asp213 (mostly by shifting scaffold design from the central piperazine ring into 4aminopiperidine) and by further exploring hydrophobic interactions to gain selectivity toward murine (m) mAMCase (e.g., OAT-177), 20 human (h) hAMCase (e.g., OAT-1441), 37 and mCHIT1 (e.g., OAT-2068) (Table 1). 38 For the future clinical candidate, we decided to focus our work on hCHIT1/ hAMCase inhibitors and progress lead compound 3. 39 The independent, very recent publication on m-and hCHIT1 selective inhibitor and its antifibrotic activity in bleomycin induced lung fibrosis model in mice was reported by Jiang et al 40 Molecule 3, compared to many others made in the program (>3K chitinase inhibitors have been synthesized and tested), has a unique in vitro profile, being a very strong inhibitor of all four isoforms of key chitinase targets, i.e., both mouse and human CHIT1 and AMCase.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Discovery of OATD-01, a First-in-Class Chitinase Inhibitor as Potential New Therapeutics for Idiopathic Pulmonary Fibrosis

et al. 2020

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Chitotriosidase (CHIT1) and acidic mammalian chitinase (AMCase) are the enzymatically active chitinases that have been implicated in the pathology of chronic lung diseases such as asthma and interstitial lung diseases (ILDs), including idiopathic pulmonary fibrosis (IPF) and sarcoidosis. The clinical and preclinical data suggest that pharmacological inhibition of CHIT1 might represent a novel therapeutic approach in IPF. Structural modification of an advanced lead molecule 3 led to the identification of compound 9 (OATD-01), a highly active CHIT1 inhibitor with both an excellent PK profile in multiple species and selectivity against a panel of other off-targets. OATD-01 given orally once daily in a range of doses between 30 and 100 mg/kg showed significant antifibrotic efficacy in an animal model of bleomycin-induced pulmonary fibrosis. OATD-01 is the first-in-class CHIT1 inhibitor, currently completed phase 1b of clinical trials, to be a potential treatment for IPF.

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“…42 In our ongoing program targeting chitinase inhibition as a potential therapeutic approach for a broad range of pulmonary, inflammatory, and fibrotic diseases, we have focused on finding specific and potent compounds toward both AMCase and CHIT1. Recently, we have reported OAT-2068 43 and OAT-177, 44 which are selective inhibitors of mouse CHIT1 (mCHIT1) and mouse AMCase (mAMCase) enzymes, respectively (Figure 1). Both compounds displayed excellent in vitro activities and pharmacokinetic (PK) profiles.…”

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confidence: 99%

Benzoxazepine-Derived Selective, Orally Bioavailable Inhibitor of Human Acidic Mammalian Chitinase

Andryianau

Kowalski

Piotrowicz

et al. 2020

ACS Med. Chem. Lett.

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Human acidic mammalian chitinase (hAMCase) is one of two true chitinases in humans, the function of which remains elusive. In addition to the defense against highly antigenic chitin and chitin-containing pathogens in the gastric and intestinal contents, AMCase has been implicated in asthma, allergic inflammation, and ocular pathologies. Potent and selective smallmolecule inhibitors of this enzyme have not been identified to date. Here we describe structural modifications of compound OAT-177, a previously developed inhibitor of mouse AMCase, leading to OAT-1441, which displays high activity and selectivity toward hAMCase. Significantly reduced off-target activity toward the human ether-a-go-go-related gene (hERG) and a good pharmacokinetic profile make OAT-1441 a potential candidate for further preclinical development as well as a useful tool compound to study the physiological role of hAMCase.

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Discovery of selective, orally bioavailable inhibitor of mouse chitotriosidase

Cited by 12 publications

References 18 publications

A New Inhibitor of Tubulin Polymerization Kills Multiple Cancer Cell Types and Reveals p21-Mediated Mechanism Determining Cell Death after Mitotic Catastrophe

A New Inhibitor of Tubulin Polymerization Kills Multiple Cancer Cell Types and Reveals p21-Mediated Mechanism Determining Cell Death after Mitotic Catastrophe

Discovery of OATD-01, a First-in-Class Chitinase Inhibitor as Potential New Therapeutics for Idiopathic Pulmonary Fibrosis

Benzoxazepine-Derived Selective, Orally Bioavailable Inhibitor of Human Acidic Mammalian Chitinase

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