OTSSP167 free base | OTS167 | CAS#1431697-89-0 | 1431698-10-0 | MELK inhibitor

MedKoo Cat#: 407423 | Name: OTSSP167 free base

Description:

WARNING: This product is for research use only, not for human or veterinary use.

OTSSP167, also known as OTS167, is an orally available inhibitor of maternal embryonic leucine zipper kinase (MELK) with potential antineoplastic activity. Upon administration, OTS167 binds to MELK, which prevents both MELK phosphorylation and activation; thus inhibiting the phosphorylation of downstream MELK substrates. This may lead to an inhibition of both cell proliferation and survival in MELK-expressing tumor cells.

Chemical Structure

OTSSP167 free base

CAS#1431697-89-0 (free base)

Theoretical Analysis

MedKoo Cat#: 407423

Name: OTSSP167 free base

CAS#: 1431697-89-0 (free base)

Chemical Formula: C25H28Cl2N4O2

Exact Mass: 486.1589

Molecular Weight: 487.43

Elemental Analysis: C, 61.60; H, 5.79; Cl, 14.55; N, 11.49; O, 6.56

Price and Availability

Size	Price	Availability
25mg	USD 250.00	2 weeks
50mg	USD 425.00	2 weeks
100mg	USD 685.00	2 weeks
200mg	USD 1,150.00	2 weeks
500mg	USD 2,450.00	2 weeks
1g	USD 3,450.00	2 weeks
2g	USD 5,250.00	2 weeks

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Related CAS #

1431698-10-0 (HCl) 1431697-89-0 (free base)

Synonym

OTSSP167 free base; OTSSP 167; OTSSP-167; OTS167; OTS-167; OTS 167.

IUPAC/Chemical Name

1-(6-(3,5-dichloro-4-hydroxyphenyl)-4-(((1r,4r)-4-((dimethylamino)methyl)cyclohexyl)amino)-1,5-naphthyridin-3-yl)ethanone

InChi Key

DKZYXHCYPUVGAF-JCNLHEQBSA-N

InChi Code

InChI=1S/C25H28Cl2N4O2/c1-14(32)18-12-28-22-9-8-21(16-10-19(26)25(33)20(27)11-16)30-24(22)23(18)29-17-6-4-15(5-7-17)13-31(2)3/h8-12,15,17,33H,4-7,13H2,1-3H3,(H,28,29)/t15-,17-

SMILES Code

CC(C1=C(N[C@H]2CC[C@H](CN(C)C)CC2)C3=NC(C4=CC(Cl)=C(O)C(Cl)=C4)=CC=C3N=C1)=O

Appearance

Solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO

Shelf Life

>2 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

Product Data

Product Data

Instruction

View handling instruction

Biological target:

OTSSP167 (OTS167) is a highly potent and ATP-competitive MELK inhibitor with IC50 value of 0.41 nM.

In vitro activity:

OTSSP167 abrogates the mitotic checkpoint at concentrations used to inhibit MELK. The abrogation is not recapitulated by RNAi mediated silencing of MELK in cells. Although OTSSP167 indeed inhibits MELK, it exhibits off-target activity against Aurora B kinase in vitro and in cells. Furthermore, OTSSP167 inhibits BUB1 and Haspin kinases, reducing phosphorylation at histones H2AT120 and H3T3 and causing mislocalization of Aurora B and associated chromosomal passenger complex from the centromere/kinetochore. Reference: PLoS One. 2016 Apr 15;11(4):e0153518. https://pubmed.ncbi.nlm.nih.gov/27082996/

In vivo activity:

When the TumorGraft volume reached 100-200 mm3, the PDX mice were intravenously treated with OTSSP167 (15 mg/kg) or vehicle once every other day for two weeks. The reaction to OTSSP167 was quantified by tumor growth inhibition (TGI). In the two MELK-positive models, TGI values were 106% and 112% at the end of drug administration (Fig.6D and 6E, right panel). In both MELK-positive cases, MELK expression was eliminated in the TumorGraft after OTSSP167 treatment but not after vehicle treatment (Fig. 6D and 6E, middle panel). Reference: Oncotarget. 2016 Feb 2;7(5):6266-80. https://pubmed.ncbi.nlm.nih.gov/26701722/

	Solvent	mg/mL	mM
Solubility
	4-methylpyridine	10.0	20.52

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 487.43 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

1. Ji W, Arnst C, Tipton AR, Bekier ME 2nd, Taylor WR, Yen TJ, Liu ST. OTSSP167 Abrogates Mitotic Checkpoint through Inhibiting Multiple Mitotic Kinases. PLoS One. 2016 Apr 15;11(4):e0153518. doi: 10.1371/journal.pone.0153518. PMID: 27082996; PMCID: PMC4833387. 2. Cho YS, Kang Y, Kim K, Cha YJ, Cho HS. The crystal structure of MPK38 in complex with OTSSP167, an orally administrative MELK selective inhibitor. Biochem Biophys Res Commun. 2014 Apr 25;447(1):7-11. doi: 10.1016/j.bbrc.2014.03.034. Epub 2014 Mar 18. PMID: 24657156. 3. Li S, Li Z, Guo T, Xing XF, Cheng X, Du H, Wen XZ, Ji JF. Maternal embryonic leucine zipper kinase serves as a poor prognosis marker and therapeutic target in gastric cancer. Oncotarget. 2016 Feb 2;7(5):6266-80. doi: 10.18632/oncotarget.6673. PMID: 26701722; PMCID: PMC4868755. 4. Chung S, Suzuki H, Miyamoto T, Takamatsu N, Tatsuguchi A, Ueda K, Kijima K, Nakamura Y, Matsuo Y. Development of an orally-administrative MELK-targeting inhibitor that suppresses the growth of various types of human cancer. Oncotarget. 2012 Dec;3(12):1629-40. doi: 10.18632/oncotarget.790. PMID: 23283305; PMCID: PMC3681500.

In vitro protocol:

In vivo protocol:

1. Li S, Li Z, Guo T, Xing XF, Cheng X, Du H, Wen XZ, Ji JF. Maternal embryonic leucine zipper kinase serves as a poor prognosis marker and therapeutic target in gastric cancer. Oncotarget. 2016 Feb 2;7(5):6266-80. doi: 10.18632/oncotarget.6673. PMID: 26701722; PMCID: PMC4868755. 2. Chung S, Suzuki H, Miyamoto T, Takamatsu N, Tatsuguchi A, Ueda K, Kijima K, Nakamura Y, Matsuo Y. Development of an orally-administrative MELK-targeting inhibitor that suppresses the growth of various types of human cancer. Oncotarget. 2012 Dec;3(12):1629-40. doi: 10.18632/oncotarget.790. PMID: 23283305; PMCID: PMC3681500.

1: Wang J, Wang Y, Shen F, Xu Y, Zhang Y, Zou X, Zhou J, Chen Y. Maternal embryonic leucine zipper kinase: A novel biomarker and a potential therapeutic target of cervical cancer. Cancer Med. 2018 Nov;7(11):5665-5678. doi: 10.1002/cam4.1816. Epub 2018 Oct 18. PubMed PMID: 30334367; PubMed Central PMCID: PMC6246930. 2: Meel MH, de Gooijer MC, Guillén Navarro M, Waranecki P, Breur M, Buil LCM, Wedekind LE, Twisk JWR, Koster J, Hashizume R, Raabe EH, Montero Carcaboso A, Bugiani M, van Tellingen O, van Vuurden DG, Kaspers GJL, Hulleman E. MELK Inhibition in Diffuse Intrinsic Pontine Glioma. Clin Cancer Res. 2018 Nov 15;24(22):5645-5657. doi: 10.1158/1078-0432.CCR-18-0924. Epub 2018 Jul 30. PubMed PMID: 30061363. 3: Okur E, Yerlikaya A. A novel and effective inhibitor combination involving bortezomib and OTSSP167 for breast cancer cells in light of label-free proteomic analysis. Cell Biol Toxicol. 2019 Feb;35(1):33-47. doi: 10.1007/s10565-018-9435-z. Epub 2018 Jun 14. PubMed PMID: 29948483. 4: Zhang Y, Zhou X, Li Y, Xu Y, Lu K, Li P, Wang X. Inhibition of maternal embryonic leucine zipper kinase with OTSSP167 displays potent anti-leukemic effects in chronic lymphocytic leukemia. Oncogene. 2018 Oct;37(41):5520-5533. doi: 10.1038/s41388-018-0333-x. Epub 2018 Jun 12. PubMed PMID: 29895969. 5: Kiseljak-Vassiliades K, Zhang Y, Kar A, Razzaghi R, Xu M, Gowan K, Raeburn CD, Albuja-Cruz M, Jones KL, Somerset H, Fishbein L, Leong S, Wierman ME. Elucidating the Role of the Maternal Embryonic Leucine Zipper Kinase in Adrenocortical Carcinoma. Endocrinology. 2018 Jul 1;159(7):2532-2544. doi: 10.1210/en.2018-00310. PubMed PMID: 29790920; PubMed Central PMCID: PMC6669820. 6: Muller J, Bolomsky A, Dubois S, Duray E, Stangelberger K, Plougonven E, Lejeune M, Léonard A, Marty C, Hempel U, Baron F, Beguin Y, Cohen-Solal M, Ludwig H, Heusschen R, Caers J. Maternal embryonic leucine zipper kinase inhibitor OTSSP167 has preclinical activity in multiple myeloma bone disease. Haematologica. 2018 Aug;103(8):1359-1368. doi: 10.3324/haematol.2017.185397. Epub 2018 May 10. PubMed PMID: 29748441; PubMed Central PMCID: PMC6068043. 7: Guan S, Lu J, Zhao Y, Yu Y, Li H, Chen Z, Shi Z, Liang H, Wang M, Guo K, Chen X, Sun W, Bieerkehazhi S, Xu X, Sun S, Agarwal S, Yang J. MELK is a novel therapeutic target in high-risk neuroblastoma. Oncotarget. 2017 Dec 20;9(2):2591-2602. doi: 10.18632/oncotarget.23515. eCollection 2018 Jan 5. PubMed PMID: 29416794; PubMed Central PMCID: PMC5788662. 8: Bolomsky A, Heusschen R, Schlangen K, Stangelberger K, Muller J, Schreiner W, Zojer N, Caers J, Ludwig H. Maternal embryonic leucine zipper kinase is a novel target for proliferation-associated high-risk myeloma. Haematologica. 2018 Feb;103(2):325-335. doi: 10.3324/haematol.2017.172973. Epub 2017 Nov 9. PubMed PMID: 29122991; PubMed Central PMCID: PMC5792277. 9: Huang HT, Seo HS, Zhang T, Wang Y, Jiang B, Li Q, Buckley DL, Nabet B, Roberts JM, Paulk J, Dastjerdi S, Winter GE, McLauchlan H, Moran J, Bradner JE, Eck MJ, Dhe-Paganon S, Zhao JJ, Gray NS. MELK is not necessary for the proliferation of basal-like breast cancer cells. Elife. 2017 Sep 19;6. pii: e26693. doi: 10.7554/eLife.26693. PubMed PMID: 28926338; PubMed Central PMCID: PMC5605198. 10: Liu H, Sun Q, Sun Y, Zhang J, Yuan H, Pang S, Qi X, Wang H, Zhang M, Zhang H, Yu C, Gu C. MELK and EZH2 Cooperate to Regulate Medulloblastoma Cancer Stem-like Cell Proliferation and Differentiation. Mol Cancer Res. 2017 Sep;15(9):1275-1286. doi: 10.1158/1541-7786.MCR-17-0105. Epub 2017 May 23. PubMed PMID: 28536141. 11: Arend KC, Lenarcic EM, Vincent HA, Rashid N, Lazear E, McDonald IM, Gilbert TS, East MP, Herring LE, Johnson GL, Graves LM, Moorman NJ. Kinome Profiling Identifies Druggable Targets for Novel Human Cytomegalovirus (HCMV) Antivirals. Mol Cell Proteomics. 2017 Apr;16(4 suppl 1):S263-S276. doi: 10.1074/mcp.M116.065375. Epub 2017 Feb 25. PubMed PMID: 28237943; PubMed Central PMCID: PMC5393402. 12: Simon M, Mesmar F, Helguero L, Williams C. Genome-wide effects of MELK-inhibitor in triple-negative breast cancer cells indicate context-dependent response with p53 as a key determinant. PLoS One. 2017 Feb 24;12(2):e0172832. doi: 10.1371/journal.pone.0172832. eCollection 2017. PubMed PMID: 28235006; PubMed Central PMCID: PMC5325553. 13: Kohler RS, Kettelhack H, Knipprath-Mészaros AM, Fedier A, Schoetzau A, Jacob F, Heinzelmann-Schwarz V. MELK expression in ovarian cancer correlates with poor outcome and its inhibition by OTSSP167 abrogates proliferation and viability of ovarian cancer cells. Gynecol Oncol. 2017 Apr;145(1):159-166. doi: 10.1016/j.ygyno.2017.02.016. Epub 2017 Feb 14. PubMed PMID: 28214016. 14: Naz F, Sami N, Naqvi AT, Islam A, Ahmad F, Imtaiyaz Hassan M. Evaluation of human microtubule affinity-regulating kinase 4 inhibitors: fluorescence binding studies, enzyme, and cell assays. J Biomol Struct Dyn. 2017 Nov;35(14):3194-3203. doi: 10.1080/07391102.2016.1249958. Epub 2016 Nov 3. PubMed PMID: 27748164. 15: Ji W, Arnst C, Tipton AR, Bekier ME 2nd, Taylor WR, Yen TJ, Liu ST. OTSSP167 Abrogates Mitotic Checkpoint through Inhibiting Multiple Mitotic Kinases. PLoS One. 2016 Apr 15;11(4):e0153518. doi: 10.1371/journal.pone.0153518. eCollection 2016. PubMed PMID: 27082996; PubMed Central PMCID: PMC4833387. 16: Chung S, Kijima K, Kudo A, Fujisawa Y, Harada Y, Taira A, Takamatsu N, Miyamoto T, Matsuo Y, Nakamura Y. Preclinical evaluation of biomarkers associated with antitumor activity of MELK inhibitor. Oncotarget. 2016 Apr 5;7(14):18171-82. doi: 10.18632/oncotarget.7685. PubMed PMID: 26918358; PubMed Central PMCID: PMC4951280. 17: Li S, Li Z, Guo T, Xing XF, Cheng X, Du H, Wen XZ, Ji JF. Maternal embryonic leucine zipper kinase serves as a poor prognosis marker and therapeutic target in gastric cancer. Oncotarget. 2016 Feb 2;7(5):6266-80. doi: 10.18632/oncotarget.6673. PubMed PMID: 26701722; PubMed Central PMCID: PMC4868755. 18: Naz F, Shahbaaz M, Bisetty K, Islam A, Ahmad F, Hassan MI. Designing New Kinase Inhibitor Derivatives as Therapeutics Against Common Complex Diseases: Structural Basis of Microtubule Affinity-Regulating Kinase 4 (MARK4) Inhibition. OMICS. 2015 Nov;19(11):700-11. doi: 10.1089/omi.2015.0111. PubMed PMID: 26565604. 19: Ramírez J, Mirkov S, House LK, Ratain MJ. Glucuronidation of OTS167 in Humans Is Catalyzed by UDP-Glucuronosyltransferases UGT1A1, UGT1A3, UGT1A8, and UGT1A10. Drug Metab Dispos. 2015 Jul;43(7):928-35. doi: 10.1124/dmd.115.063271. Epub 2015 Apr 13. PubMed PMID: 25870101; PubMed Central PMCID: PMC4468433. 20: Ganguly R, Hong CS, Smith LG, Kornblum HI, Nakano I. Maternal embryonic leucine zipper kinase: key kinase for stem cell phenotype in glioma and other cancers. Mol Cancer Ther. 2014 Jun;13(6):1393-8. doi: 10.1158/1535-7163.MCT-13-0764. Epub 2014 May 2. Review. PubMed PMID: 24795222; PubMed Central PMCID: PMC4048631.