MEISi

First-in-class, selective, drug-like small molecule MEIS inhibitors 

 MEIS Protein as a drug target

MEIS family of proteins are found to be important regulators of homeostasis. Studies in the last decade have shown that Meis1 has crucial roles in cardiac regeneration, stem cell function, and tumorigenesis. MEIS proteins are associated with limited cardiac regeneration, limited stem cell proliferation and cancer progression.

MEIS proteins could be therapeutically targeted to develop therapies for cardiovascular diseases, bone failure, and cancer. Meis1 was first discovered in BXH-2 mouse leukemia model. Studies in the last decade have shown that Meis1 has crucial roles in cellular metabolism, redox state, and tumorigenesis. Meis1 maintains cytoplasmic glycolysis through transactivation of hypoxic tumor markers, namely Hif-1α and Hif-2α. MEIS1 along with other homeobox proteins (PBX and HOXA) often found to be driving hematopoietic transformation in MLL-rearranged leukemia and described as an oncogene. Intriguingly, a high level of Meis1 expression was found to be associated with resistance to conventional chemotherapies (Reviewed in  Current drug targets).

​About MEIS and Development of MEIS inhibitors

Meis1 is a member of three-amino-acid loop extension (TALE) homeodomain transcription factors. Studies in the last decade have shown that Meis1 has crucial roles in cardiac regeneration, stem cell function, and tumorigenesis. We have recently demonstrated that knocking out of Meis1 in adult cardiomyocytes resulted in the induction of cardiomyocyte proliferation. This suggests that targeting of Meis1 might be utilized in the manipulation of cardiomyocyte cell cycle post cardiac injuries. In addition, hematopoietic stem cell (HSC) specific deletion of Meis1 leads to in vivo expansion of HSCs pool. Thus, targeting Meis1 may lead to not only cell cycle entry but also ex vivo and in vivo expansion of HSCs. On the other hand, Meis1 transcriptionally regulates the expression of hypoxic tumor markers, namely Hif-1α and Hif-2α. Hif-1α and Hif-2α are involved in the induction of cytoplasmic glycolysis and scavenging of reactive oxygen species (ROS), respectively. Studies highlight emerging roles of Meis1 towards development of new therapeutic approaches in the treatment of myocardial injuries, bone failure, and cancer (Reviewed in  Current drug targets).

​Development of MEIS inhibitors

We have performed a number of analysis to develop small molecule MEIS inhibitors, which includes but not limited to;

1. in silico drug screening
2. in vitro luciferase assays
3. PCR pathway analyses
4. ex vivo validation studies
5. in vivo validation studies​​

​We have performed in silico screening of over 1 million small molecules which target MEIS homeodomain and are conducted in comparison to the other TALE homeodomains, have enabled to determine MEIS-specific hits

By means of the in vitro luciferase studies conducted, the MEIS inhibitors which we have named as MEIS inhibitor-1 (MEISi-1) and MEIS inhibitor-2 (MEISi-2) were determined for the first time. These inhibitors (MEISi-1 and MEISi-2) inhibit MEIS luciferase reporter (Mahmoud &Kocabas et al, Nature, 2012) in a dose-dependent manner. 

It was found that MEISi-1 and MEISi-2, which are among the developed MEIS inhibitors, reduce expression of p21, Hif-1alpha (Hif-1α), Hif-2alpha (Hif-2α) genes in the Meis1 pathway in vitro and in vivo. 

MEISi related awards

1. Best Poster Award. Fatih Kocabas, et al. Meis1 is a key regulator of post-natal cardiomyocyte cell cycle arrest. Basic Cardiovascular Sciences 2012 Scientific Sessions, New Orleans, Louisiana, USA (July 23-26, 2012). Circulation Research. 111(4_MeetingAbstracts) Supplement 1, July 20, 2012. [Award winning Abstract] Awardee: Fatih Kocabas.
2. Oral Presentation Award. "MEISi". Biruni University, Computer Aided Drug Design Meeting, May 2016. Istanbul, Turkey. Awardee: Fatih Kocabas.
3. Best poster award. Identification of Cardiogenic and Hematopoietic Inhibitors of Meis1. 2nd International Congress of Stem Cell and Cellular Therapies. October 2015. Antalya, Turkey. Awardee: R.D. Turan and Fatih Kocabas.
4. Oral Presentation Award. "Small Molecule Induced Hematopoietic Stem Cell Expansion". MEMBS 2015 Congress. Istanbul, Turkey. Awardee: Fatih Kocabas.
5. Career Development Award: TUBITAK ARDEB 3501. 2016-2018. PI: Fatih Kocabas.
6. ​Young Researcher Award: Turkish Society of Hematology (Türk Hematoloji Derneği) Research Award. 2016-2017.  PI: Fatih Kocabas.

Patents

1. National Patent: 2016/16602, "A COMBINATION INHIBITING MEIS PROTEINS". Pending.
2. PCT 25418.57, PCT/TR2017/050445 "A COMBINATION INHIBITING MEIS PROTEINS". Pending.

MEIS and MEISi related publications

1. Fatih Kocabas (co-first author), Ahmed I Mahmoud, Shalini A. Muralidhar, Wataru Kimura, Ahmed S. Koura, Suwannee Thet, Enzo R. Porrello, and Hesham A. Sadek. Meis1 regulates postnatal cardiomyocyte cell cycle arrest. Nature 497, no. 7448 (2013): 249-253. [Nature Impact Factor: 42.351] PDF
2. Fatih Kocabas, Junke Zheng, Suwannee Thet, Neal G. Copeland, Nancy A. Jenkins, Ralph J. DeBerardinis, Chengcheng Zhang, and Hesham A. Sadek. "Meis1 regulates the metabolic phenotype and oxidant defense of hematopoietic stem cells." Blood (2012). [Blood Impact Factor: 9.898] PDF
3. Fatih Kocabas(co-first author), Tugba Simsek, Junke Zheng, Ralph J. DeBerardinis, Ahmed I. Mahmoud, Eric N. Olson, Jay W. Schneider, Cheng Cheng Zhang, and Hesham A. Sadek. "The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche." Cell Stem Cell 7, no. 3 (2010): 380-390. [Cell Stem Cell Impact Factor: 25.421] PDF
4. Merve Aksoz, Raife Dilek Turan, Esra Albayrak, Fatih Kocabaş*. Emerging Roles of Meis1 in Cardiac Regeneration, Stem Cells, and Cancer. Current drug targets. 2017 Jul 24. doi: 10.2174/1389450118666170724165514 Full text
5. Fatih Kocabas*. Emerging Roles of MEIS1 in Hematopoiesis and Heart Regeneration. ISBN 978-3-659-59658-2. LAP LAMBERT Academic Publishing, Germany. February 23, 2015. Link
6. Fatih Kocabas*. MEIS1: At the Crossroads between Metabolic and Cell Cycle Regulation. PhD diss., 2013. UT Southwestern Electronic Theses and Dissertations. PDF​
7. Şeyma Nur Eren, Raife Dilek Turan, Fatih Kocabaş. Hücre ekspansiyonunda etkin MEIS inhibitorlerinin geliştirilmesi.  Hücresel İmmunoterapi sempozyumu. 20-22 October 2017. Trabzon, Turkey
8. Semih Arbatlı, Raife Dilek Turan, Galip Servet Aslan, Esra Albayrak, Serdar Durdağı, Fatih Kocabaş. Identification of Cardiogenic and Hematopoietic MEIS Inhibitors that Enhance Cellular Proliferation and HDR Gene Expression. 5th International Bau Drug Design Congress. 19-21 October, 2017. Istanbul, Turkey
9. Semih Arbatlı, Merve Uslu, Fatih Kocabaş. Identification of Cas9 small molecule inhibitors.Identification of Cardiogenic and Hematopoietic MEIS Inhibitors that Enhance Cellular Proliferation and HDR Gene Expression. 5th International Bau Drug Design Congress. 19-21 October, 2017. Istanbul, Turkey
10. Fatih Kocabaş, Semih Arbatlı, Raife Dilek Turan, Galip Servet Aslan, Esra Albayrak, Merve Uslu, Serdar Durdağı, Zafer Gülbaş. Identification of Hematopoietic and Cardiogenic MEIS Inhibitors that Enhance Cellular Proliferation and HDR Gene Expression. 5th International Congress of the Molecular Biology Association of Turkey (MolBiyoKon’17). 8-10 September 2017. Istanbul, Turkey
11. Raife Dilek Turan, Enes K. Ergin, Fatih Kocabas. The Establishment of Homeobox Family Inhibitor Library and Meis1 Reporter Assays. 3rd International BAU Drug Design Congress. Oct 1-3. 2015. Istanbul.
12. Fatih Kocabas, Ahmed I Mahmoud, Shalini Muralidhar, Suwannee Thet, Enzo R. Porrello, Eric Olson, and Hesham A. Sadek. Meis1 is a key regulator of post-natal cardiomyocyte cell cycle arrest. Basic Cardiovascular Sciences 2012 Scientific Sessions, New Orleans, Louisiana, USA (July 23-26, 2012). Circulation Research. 111(4_MeetingAbstracts) Supplement 1, July 20, 2012. [Award winning Abstract] [Circulation Research Impact Factor: 9.489]