GPCR, allosteric modulation, target binding kinetics, small molecule
Our Focus
I focus on the theme “Novel receptor concepts to target membrane proteins” with the ultimate aim to make medicines work better. Thus, having the potential for a large societal impact. I have selected membrane-bound proteins, such as G protein-coupled receptors (GPCRs), as many drugs act via these and they play a pivotal role in disease. I have been able to develop an array of novel in vitro equilibrium and kinetic binding assays, as well as (label-free) functional assays to investigate “Novel Mechanisms of Action” (i.e. concepts) to target membrane proteins, such as target binding kinetics and allosteric modulation. My research can basically be split in two lines: 1) Intervening with receptor function by small molecules, and 2) Understanding (variant) receptor pharmacology.
To this end, we combine and integrate different expertise and research domains relevant for modern future molecular pharmacology, such as receptor pharmacology, molecular and cellular biology, organic chemistry and computational chemistry. Here the implementation of future key technologies and methodologies is crucial, such as high throughput kinetic binding and signalling assays, both at cell membranes and on living cells. My team collaborates with crystallographers, cell biologists and in vivo pharmacologists, both from academia and pharmaceutical industry. Of note, medicinal chemistry research in academia typically has few, if any, links with the clinic, but the concepts that I work on have a large translational potential. Hence, I keep a keen eye on collaborating within Oncode, but also with research hospitals and pharmaceutical companies to go from an idea to proof-of-concept and continue to make my research translational in nature, next to being fundamental.
The concepts that I work on are in principle ‘disease-agnostic’, i.e. the proteins that I have selected have a place in many diseases. However, I am applying (part of) my research lines to cancer. This is actually quite logical, as it is becoming clear that GPCRs and their subsequent signalling mechanisms play an important role in regulating cellular functions, which are related to known hallmarks of cancer. Notably, GPCRs are not only (over-)expressed on cancer cells themselves, but also on cell-types in the tumour microenvironment, including cancer-associated fibroblasts and inflammatory cells. Moreover, recent work has shown that GPCRs present in patient isolates are sensitive to mutation, i.e. GPCRs are mutated in an estimated 20% of all cancers. In addition, we and others have seen that GPCRs can have a wide variety of post translational modifications (PTMs) such as N-glycosylation and phosphorylation, where these PTM “patterns” differ in various cell backgrounds. This fuels further interest in the role of GPCRs in tumour biology.
The main scientific questions are:
- Which kind of chemical modality, e.g. allosteric, covalent, is best suited to efficaciously target a protein?
- Does in vitro optimization of a drug’s mechanism of action benefit in vivo efficacy?
- Where is the drug target expressed and in what form?
- How does a mutation or PTM affect a drug target’s pharmacology? And does this alter its druggability?
About Laura Heitman
Laura Heitman
My Research
I focus on the theme “Novel receptor concepts to target membrane proteins” that has the potential for a large societal impact. I have selected membrane-bound proteins, such as G protein-coupled receptors (GPCRs), as many drugs act via these. I have been able to develop an array of novel in vitro equilibrium and kinetic binding assays, as well as (label-free) functional assays to investigate my research theme, with the ultimate aim to make medicines work better.
Within the field of GPCRs I am both nationally and internationally recognized as a leader, as shown by several top publications in this field (see ‘selected publications’ below). From the start of my career, i.e. as a PhD student, and by obtaining several competitive research grants (e.g. NWO-VENI, NWO-VIDI, IMI-K4DD), I have been able to independently build my own research line along two novel receptor concepts in particular, i.e. ‘Allosteric modulation of GPCRs’ and ‘Drug-target binding kinetics’. Together, these two concepts culminated in a 2016 Nature paper where we were able to identify a novel intracellular binding site for small molecule antagonists at the chemokine receptor CCR2. Interestingly, a consequence of both concepts is so-called insurmountable antagonism, i.e. antagonists that cannot be disrupted/counteracted by high local concentrations of the endogenous receptor agonist that is often causal to.
To this end, we combine and integrate different expertise and research domains relevant for modern future molecular pharmacology, such as receptor pharmacology, molecular and cellular biology, organic chemistry and computational chemistry. Here the implementation of future key technologies and methodologies is crucial, such as high throughput kinetic binding and signaling assays, both at cell membranes and on living cells. My team collaborates with crystallographers, cell biologists and in vivo pharmacologists, both from academia and pharmaceutical industry. Of note, medicinal chemistry research in academia typically has few, if any, links with the clinic, but the concepts that I work on have a large translational potential. Hence, I keep a keen eye on collaborating with research hospitals and pharmaceutical companies to go from an idea to proof-of-concept and continue to make my research translational in nature, next to being fundamental.
Awards
2018: Oncode Junior Investigator (600 k€)
2018: Prix Galien Research award 2018 (runner-up)
2018: NWO-VIDI “Rethinking drug discovery – target binding kinetics as an essential paradigm” (800 k€)
2018: Prize for a Young Medicinal Chemist in Academia by European Federation of Medicinal Chemistry (runner-up)
2017: MedChemComm Emerging Investigator 2017 award by Royal Society of Chemistry
2015: RPF “Establishment of structure-kinetics relationships to elucidate the mode of action of CB2 ligands” (233 k€)
2013: IWT-O&O “Kinetic profiling as a novel concept for GPCR drug action” (294 k€)
2012: Best lecturer at Leiden University by the Leiden Student Council (runner-up)
2011: IMI "Kinetics for Drug Discovery" (1 M€)
2010: NWO-VENI “Why do drugs fail in man? Drug-target residence time as a novel parameter in drug design and discovery” (250 k€)
2009: “Discoverer of the Year 2009”-award from the Faculty of Science of Leiden University
Key Publications
Zheng Y, Qin L, Zacarías NV, de Vries H, Han GW, Gustavsson M, Dabros M, Zhao C, Cherney RJ, Carter P, Stamos D, Abagyan R, Cherezov V, Stevens RC, IJzerman AP, Heitman LH#, Tebben A, Kufareva I#, Handel TM#. Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists. Nature. 2016, 540, 458 (#shared senior author)
Liu W, Chun E, Thompson AA, Chubukov P, Xu F, Katritch V, Han GW, Roth CB, Heitman LH, IJzerman AP, Cherezov V, Stevens RC. Structural basis for allosteric regulation of GPCRs by sodium ions. Science. 2012, 337, 232-236
Soethoudt M*, Grether U*, Fingerle J*, Grim TW, Fezza F, de Petrocellis L, Ullmer C, Rothenhausler B, Perret C, van Gils N, Finlay D, MacDonald C, Chicca A, Gens MD, Stuart J, de Vries H, Mastrangelo N, Xia L, Alachouzos G, Baggelaar M, Martella A, Mock ED, Deng H, Heitman LH#, Connor M#, di Marzo V#, Gertsch J#, Lichtman AH#, Maccarrone M#, Pacher P#, Glass M#, van der Stelt M#. Cannabinoid CB2 Receptor Ligand Profiling Reveals Biased Signaling and Off-target Activity: Implications for Drug Discovery. Nat Commun. 2017, 8, 13958 (#shared senior author)
Bot I*, Ortiz Zacarías NV*, de Witte WE, de Vries H, van Santbrink PJ, van der Velden D, Kröner MJ, van der Berg DJ, Stamos D, de Lange EC, Kuiper J, IJzerman AP, Heitman LH. A novel CCR2 antagonist inhibits atherogenesis in apoE deficient mice by achieving high receptor occupancy. Sci. Rep. 2017, 7, 52
Vlachodimou A, IJzerman AP, Heitman LH.Label-free detection of transporter activity via GPCR signalling in living cells: A case for SLC29A1, the equilibrative nucleoside transporter 1. Sci Rep. 2019, 9, 13802
Members
| Laura Heitman Group leader | Bert Beerkens Phd Student | Cas van der Horst Research Technician |
| Daan van der Es Assistant Professor | Inge Snijders PhD student | Khaled Essa Phd Student |
| Lisa de Koning PhD student | Natalia Ortiz Zacarias PostDoc | Rongfang Liu Technician |
| Sean McKenna PostDoc | Tamara Mocking Dr. | Yao Yao Phd Student |