Grembecka/Cierpicki Lab

Home Jolanta Grembecka Tomasz Cierpicki Lab Projects Publications Lab Members Positions Available Lab News

 

Nov 2016

We have published paper "BMI1 regulates PRC1 architecture and activity through homo- and hetero-oligomerization" in Nature Communictions.

Sep 2016

We have published review H3K36 methyltransferases as cancer drug targets: rationale and perspectives for inhibitor development in Future Medicinal Chemistry.

We published development of potent BCL6 inhibitor in collaboration with groups from Cornell and University of Maryland.

May 2016

David Rogawski defended his PhD thesis. Congratulations Dave!

 Jan 2016

We published paper "Property focused structure-based optimization of small molecule inhibitors of the protein-protein interaction between menin and Mixed Lineage Leukemia (MLL)" in the Journal of Medicinal Chemistry.

Featured on the cover!

Nov 2015

We determined structure of ZMIZ1 TPR domain and published paper in collaboration with Mark Chiang: The PIAS-like Coactivator Zmiz1 Is a Direct and Selective Cofactor of Notch1 in T Cell Development and Leukemia. Published in Immunity.

Aug 2015

Our manuscript "Two loops undergoing concerted dynamics regulate activity of the ASH1L histone methyltransferase" has been published in Biochemistry.

Our study "Rational design of orthogonal multipolar interactions with fluorine in protein-ligand complexes" has been published in Journal of Medicinal Chemistry, selected as Editor's choice.

July 2015

Felicia Gray defended her PhD thesis: "Dissecting Bmi1 protein-protein interactions through chemical biology". Congratulations Felicia!

June 2015

We have published study demonstrating that menin-MLL inhibitors block activity of MLL fusion proteins in a mechanism independent on fusion partner. Published in Leukemia.

May 2015

George Lund defended his PhD dissertation: "Targeting CDC25B-CDK2/CyclinA Activity Using Chemical Biology Approaches".

Congratulations George!

April 2015

Our menin-MLL inhibitor program has been featured as cover story in BioCentury Innovations

Dr. Chinnaiyan's lab discovered role of menin and demonstrated efficacy of menin inhibitors in castrate resistant prostate cancer. Study published in Nature Medicine.

March 2015

Our team work resulted in development of potent inhibitors of menin-MLL interaction with strong efficacy in animal models of leukemia. Published in Cancer Cell

We have licensed menin-MLL inhibitors to Kura Oncology for further development.

Feb 2015

Jola is co-author on study to develop small molecule inhibitors of CBFB-SMMHC: "A small-molecule inhibitor of the aberrant transcription factor CBFβ-SMMHC delays leukemia in mice" published in Science.

Jan 2015

We published review Targeting protein–protein interactions in hematologic malignancies: still a challenge or a great opportunity for future therapies? in Immunological Reviews

Dec 2014

Our study Inhibition of CDC25B Phosphatase Through Disruption of Protein-Protein Interaction has been published in ACS Chemical Biology.

Nov 17th 2014

Jola has been elected to the University of Michigan Medical School "League of Research Excellence". Congratulations to Jola!

Oct 2014

Our study "The same site on LEDGF IBD domain represents therapeutic target for MLL leukemia and HIV" has been published in Blood. 

Apr 21 2014

George's publication "Solution NMR studies reveal no global flexibility in the catalytic domain of CDC25Bhas been published in journal Proteins.

Congratulations to George!

Our review "Challenges and opportunities in targeting the menin-MLL interaction" has been published in Future Medicinal Chemistry

1. Targeting menin-MLL interaction in leukemia
 

Menin functions as a critical oncogenic cofactor of mixed lineage leukemia (MLL) fusion proteins in the
development of acute leukemias. Inhibition of the menin interaction with MLL fusion proteins represents
a very promising strategy to reverse their oncogenic activity. Therefore, small molecule inhibitors of
menin-MLL interaction might became new therapeutic agents for leukemias with MLL translocations.
 
In our laboratory we determined the first three dimensional structure of menin and identified the first
small molecule inhibitors of the menin-MLL protein-protein interaction. Through extensive medicinal
chemistry work, we optimized these compounds resulting in the menin-MLL inhibitors that demonstrate
nanomolar activity in vitro and in MLL leukemia cells and substantially block progression of acute
leukemia in mice models of MLL leukemia. These compounds are currently in advanced pre-clinical
studies to develop clinical leads candidates as a potential therapeutic strategy for acute leukemia
patients with translocations of the MLL gene.

Selected publications
 

1.  Shi A, Murai MJ, He S, Lund G, Hartley T, Purohit T, Reddy G, Chruszcz M, Grembecka J and
Cierpicki T. (2012) Structural insights into inhibition of the bivalent menin-MLL interaction by small
molecules in leukemia
. Blood.120, 4461

This article has been selected as plenary paper and featured on the cover of Blood


2. Grembecka J, He S, Shi A, Purohit T, Muntean AG, Sorenson RJ, Showalter HD, Murai M, Belcher
A, Hartley T, Hess JL, Cierpicki T. (2012) Menin-MLL Inhibitors Reverse Oncogenic Activity of
MLL Fusion Proteins in Leukemia
Nature Chem. Biol, 8, 277-284.

This publication was highlighted in Nat Rev Cancer. 2012, 12 (3):154 and Nat Rev Drug Discov.
2012, 11(3):190.


3. Murai MJ, Chruszcz M, Reddy G, Grembecka J, Cierpicki T. (2011). Crystal structure of Menin
reveals the binding site for mixed lineage Leukemia (MLL) protein
J Biol Chem. 286, 31742-8.


4. Grembecka J, Belcher AM, Hartley T, Cierpicki T. (2010) Molecular basis of the Mixed Lineage
Leukemia (MLL) - menin interaction: implications for targeting MLL leukemias
J. Biol. Chem.
285:40690

 

Studies using our menin inhibitors

 

1. Kittan et al. Plos ONE, 2013

2. Sio et al. Cancer Res, 2013

3. Gao et al. J. Hepatology, 2014

4. Chamberlain et al. JCI, 2014

5. Funato et al. Science, 2014

6. Wijeweera et al. BBA, 2015

 

2. Fragment-based ligand discovery


Fragment-based drug discovery (FBDD) is a powerful approach to discover new leads for biological
targets. FBDD approach constitutes an excellent alternative to the high-throughput screening (HTS) as
there is a higher probability to identify efficient fragment-like small molecule ligands forming optimal
contacts with the protein comparing to the more complex molecules from HTS.


In our laboratory, we acquired a collection of approximately 1,600 fragment like compounds
based on commercial sources as well as from in house synthesized compounds. We perform NMR
screening using 600 MHz Bruker spectrometer equipped in cryogenic probe and SamlpeJet automation.
Our set-up allows for rapid and fully automated screening of large number of samples.


We are exploring fragment screening in order to develop small molecule inhibitors of protein-
protein interactions, including LEDGF and CDC25B. Importantly, fragment screening is a powerful
method to rapidly test ligandability of protein targets.

We are interested in collaborations to explore new targets!

3. Development of new methodology to identify disordered fragments in globular proteins

Application of our method: identification of disordered regions in human menin. A) Assigned 2D 13C CACO (blue)

and CBCACO (red) NMR spectra for 13C,15N menin. B) Disorder prediction from the DISOPRED2 server for the menin.

The predicted disordered regions are highlighted in yellow. Experimentally observed disordered fragments are boxed in red,

and the well-ordered fragment is boxed in blue. C) Crystal structure of human menin showing disordered fragments

observed in 13C-detected NMR experiments (red). Predicted disordered residues 204–213 (blue) belong to

a structured loop within the protein. Figure from Gray et al.