EFMC International Symposium on Medicinal Chemistry
- September 1st-5th, 2024
- Rome, Italy
Schrödinger is excited to be participating in the EFMC International Symposium on Medicinal Chemistry taking place on September 1st – 5th in Rome, Italy. Join us for a presentation and workshop by Schrödinger scientists. Stop by booth #60 to speak with Schrödinger scientists.
Workshop: Prioritizing DLK Inhibitors for Potency, Selectivity, and Brain-penetration: a Digital Chemistry Design Challenge
Speakers:
Guillaume Paillard, Lead Customer Success Manager, Schrödinger
Jonas Kaindl, Senior Scientist II, Schrödinger
Abstract: In this hands-on workshop, we will use Schrödinger’s LiveDesign platform to design and triage DLK inhibitors using a series of predictive models. We will highlight how LiveDesign can be used to identify and address program challenges as well as predict the various different endpoints to allow for informed synthesis decisions. The workshop will feature the following capabilities:
– Interactive 2D/3D design with Ligand Designer
– Substructure filtering and structurally-aware formulas for labeling subseries
– Use of forms view and plotting to identify correlations between calculated and experimental data points
– Integration of advanced computational methods like E-sol for predicting Kpu,u and FEP+ for predicting binding affinity
– Development of MPO scores for prioritizing synthesis decisions
The workshop will be concluded with a design challenge that is aimed to identify selective and potent inhibitors that match the developed MPO.
Accelerated In Silico Discovery of SGR-1505: a Potent Malt1 Allosteric Inhibitor for the Treatment of Mature B-cell Malignancies (LE063)
Speaker:
Dr. Michael Trzoss, Principal Scientist, Schrödinger
Abstract: MALT1 (Mucosa-associated lymphoid tissue lymphoma translocation protein 1) is a component of the MALT1-BCL10-CARD11 complex downstream from the Bruton Tyrosine Kinase (BTK) on the B-cell receptor signaling pathway. MALT1 is a key mediator of nuclear factor kappa B (NF-κB) signaling, which is the main driver of a subset of B-cell lymphomas. MALT1 is considered a potential therapeutic target for several subtypes of non-Hodgkin’s B-cell lymphomas and chronic lymphocytic leukemia (CLL), including tumors with acquired BTK inhibitor (BTKi) resistance. Constitutive activation of the NF-κB is a molecular hallmark of activated B cell-like diffuse large B cell lymphoma (ABC-DLBCL), and MALT1 may have utility as a treatment option for ABC-DLBCL. Furthermore, a third-party MALT1 inhibitor recently showed strong anti-tumor activity in mature B cell malignancies from Phase 1 studies.
By applying advanced physics-based modeling techniques, including combining free energy calculations with machine learning methods and chemistry-aware compound enumeration workflow, the team explored extensive sets of de novo design ideas to quickly identify a novel hit series with an in vivo tool molecule to establish an in vivo PD and efficacy mouse model early on in the project. Multi-parameter optimization (MPO) allowed efficient prioritization of molecules with good potency and drug-like properties during lead optimization. This led to the discovery of a highly potent MALT1 inhibitor, SGR-1505, with a well-balanced property profile in under a year, with only 78 compounds synthesized in the lead series and 129 compounds overall. SGR-1505 is a potent and orally available allosteric MALT1 inhibitor. It demonstrated strong anti-tumor activity alone and in combination with BTK inhibitors in multiple in vivo B-cell lymphoma xenograft models. Currently, a Phase 1 clinical trial with SGR-1505 in patients with mature B-cell neoplasms is ongoing (NCT05544019).