OTSSP167 HCl
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Hodoodo CAT#: H406520

CAS#: 1431698-10-0 (HCl)

Description: 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

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OTSSP167 HCl
CAS# 1431698-10-0 (HCl)

Theoretical Analysis

Hodoodo Cat#: H406520
Name: OTSSP167 HCl
CAS#: 1431698-10-0 (HCl)
Chemical Formula: C25H29Cl3N4O2
Exact Mass: 0.00
Molecular Weight: 523.880
Elemental Analysis: C, 57.32; H, 5.58; Cl, 20.30; N, 10.69; O, 6.11

Price and Availability

Size Price Availability Quantity
5mg USD 90 Ready to ship
10mg USD 150 Ready to ship
25mg USD 250 Ready to ship
50mg USD 450 Ready to ship
100mg USD 750 Ready to ship
200mg USD 1350 Ready to ship
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Related CAS #: 1431698-10-0 (HCl)   1431697-89-0 (free base)  

Synonym: OTSSP167; OTSSP-167; OTSSP 167; OTS167; OTS-167; OTS 167; OTSSP167 HCl; OTS167 HCl; OTSSP167 hydrochloride

IUPAC/Chemical Name: 1-(6-(3,5-dichloro-4-hydroxyphenyl)-4-(((1r,4r)-4-((dimethylamino)methyl)cyclohexyl)amino)-1,5-naphthyridin-3-yl)ethanone hydrochloride

InChi Key: XDGWHISAOWEFML-BFLZMHAMSA-N

InChi Code: InChI=1S/C25H28Cl2N4O2.ClH/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);1H/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.[H]Cl

Appearance: Light yellow 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, not in water

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:   Related CAS# 1431698-10-0 (OTSSP167 HCl salt); 1431697-89-0 (OTSSP167 free base)      

Biological target: OTSSP167 hydrochloride is a MELK inhibitor with an IC50 value of 0.41 nM.
In vitro activity: The effects of the MELK inhibitor OTSSP167 on the proliferation of osteoclast progenitor cells and on the differentiation into osteoclasts were studied. Treatment of RAW264.7 cells with 25 nM OTSSP167 for 24 hours resulted in decreased MELK protein levels (Figure 1B). The effect of continuous OTSSP167 treatment on RAW264.7 and human PBMC (peripheral blood mononuclear cell) viability was assessed, and it was found that the viability of both osteoclast progenitor populations decreased (IC50: 12.8 nM and 43.2 nM, respectively) (Figure 1C). This coincided with an induction of G2/M cell cycle arrest (Online Supplementary Figure S1A). The decrease in progenitor viability corresponded with a decrease in both human (Figure 1D and and1F)1F) and murine (Figure 1E and 1H) osteoclast differentiation following continuous OTSSP167 treatment. Although the number of osteoclasts decreased, osteoclast size was markedly increased in human cultures treated with 10 nM OTSSP167, with a corresponding increase in the number of nuclei per osteoclasts (Figure 1G). This was not the case for RAW264.7 osteoclast cultures (Figure 1I). Reference: Haematologica. 2018 Aug;103(8):1359-1368. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6068043/
In vivo activity: The potential of OTSSP167 as a therapy for MMBD (multiple myeloma bone disease) was assessed in vivo using the 5TGM.1 MM model. OTSSP167 treatment prevented the development of MMBD and this effect was similar at all dosing schedules tested (Figure 5A). OTSSP167 reduced the number of cortical perforations in MM-bearing mice (Figure 5B), without affecting cortical thickness (Ct.Th) (Online Supplementary Figure S1E). The loss of trabecular bone volume (Tb.BV/TV) that occurs in MM-bearing mice compared to healthy controls was completely prevented following treatment with OTSSP167 (Figure 5C). This was due to an increase in the number of trabeculae (Tb.N) (Figure 5D) and a decrease in trabecular separation (Tb.Sp) (Online Supplementary Figure S1F). As a result, trabecular connectivity density (Conn.Dn) was similar to healthy mice in OTSSP167-treated MM-bearing mice (Online Supplementary Figure S1G). Trabecular thickness was not affected in MM-bearing mice (Online Supplementary Figure S1H). Importantly, the observed prevention of MMBD in these mice does not appear to be solely due to a decreased tumor load following OTSSP167 treatment, as MMBD was prevented at a dose (7.5 mg/kg/2d) which had no effect on tumor load (Figure 5E). Reference: Haematologica. 2018 Aug;103(8):1359-1368. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6068043/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 30.0 57.30

Preparing Stock Solutions

The following data is based on the product molecular weight 523.88 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.

Recalculate based on batch purity %
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. 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. PMID: 29748441; PMCID: PMC6068043. 2. 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. PMID: 29895969.
In vitro protocol: 1. 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. PMID: 29748441; PMCID: PMC6068043. 2. 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. PMID: 29895969.
In vivo protocol: 1. 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. PMID: 29748441; PMCID: PMC6068043.

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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.