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>>> On Oct 13, the Schrödinger team published a research paper in the Journal of Medicinal Chemistry describing an integrated drug discovery strategy combining computer-aided drug design (CADD), free energy perturbation (FEP+) calculations, multiparameter optimization (MPO), and experimental validation. Through this approach, the team explored a vast array of de novo design ideas, rapidly identifying a novel hit series. Ultimately, they discovered SGR-1505, a highly potent and well-balanced MALT1 inhibitor. 
>>> The compound demonstrated significant antitumor activity alone and in combination with BTK inhibitor in multiple in vivo B-cell lymphoma xenograft models and progressed to a phase 1 clinical trial in patients with mature B-cell neoplasms.

Introduction

Mucosa-associated lymphoid tissue protein 1 (MALT1) is a key component of the CARD11-BCL10-MALT1 (CBM) complex downstream from BTK on the B-cell receptor signaling pathway. It is a key mediator of NF-κB signaling and considered a potential therapeutic target for several subtypes of non-Hodgkin’s B-cell lymphomas.

Limitations of current MALT1 inhibitors

·First-generation MALT1 inhibitors:
1) peptide-derived irreversible inhibitors (e.g., Z-VRPR-FMK derivatives), which have poor cell permeability and poor drug-like properties; 2) small-molecule covalent inhibitors (e.g., MI-2), which suffer from low biochemical potency and specificity.

·Next-generation allosteric inhibitors:
1) exemplified by thioridazine, which binds to the MALT1 allosteric site and non-competitively blocks its activity; 2) several candidates (e.g., MLT-748, JNJ-67856633, ONO-7018) are in preclinical or clinical development. Nevertheless, the rational design of such allosteric agents remains highly challenging.

Discovery of SGR-1505

1. De Novo Design Guided by AI

Aiming to design potent, highly selective, and orally bioavailable MALT1 allosteric inhibitors, the research team divided the MALT1 allosteric pocket into three regions based on the co-crystal structure of Novartis’ inhibitor MLT-748 (PDB: 6H4A): 
Core 1, a hydrophobic pocket normally occupied by Trp580 in the apo protein;
Linker, containing the key hydrogen-bond residue Glu397;
Core 2, which is partially solvent-exposed and located in the vicinity of the unstructured and mostly unresolved C-terminus tail. (Fig. 1). 

Fig. 1. Cocrystal structure of MLT-748 (green) in complex with MALT1 (PDB ID: 6H4A) (gray)

2. FEP+ Guided Discovery of Tricyclic Urea Novel Series

The team first integrated public information, including cocrystal structures of known MALT1 inhibitors, to build and validate a reliable free energy perturbation (FEP+) model that accurately predicts ligand binding affinities. Using compound 1 as the starting point, and while initially keeping the Core 2 region constant, the researchers introduced diverse modifications to the Linker and Core 1 regions to generate novel MALT1 inhibitors (Fig. 2). In the Linker region, they alkylated urea NH groups to remove one H-bond donor, employed urea isosteres, or cyclized the urea NH onto either Core 1 or Core 2. A total of ~1,400 ideas were generated; after initial filtering and docking, ~1,300 were evaluated by FEP+, and the top 37 designs were prioritized to synthesis.

This effort culminated in the discovery of the lead compound 2 (Fig. 2), a tricyclic urea that maintains nanomolar potency (IC₅₀ = 18 nM) via a single hydrogen bond to Glu397 and exhibits superior chemical stability compared with related analogues. A co-crystal structure confirmed the predicted binding mode.

Fig. 2. SAR of FEP+ Driven De Novo Core Design Ideas with Core 1 and Linker Changes

3. FEP+ Guided Potency Improvement and Lead Optimization Using Multiparameter Optimization (MPO)

The team next probed the small hydrophobic pocket surrounding the gem-dimethyl substituents (R1 and R2) of lead compound 2 to improve potency (Fig. 3). About 300 analogs bearing diverse R1/R2 groups were evaluated by FEP+, and the ten top-scoring designs were advanced to synthesis. Installation of a trifluoromethyl (CF₃) group at the quaternary carbon—compound 11—delivered single-digit nanomolar potency (MALT1 IC₅₀ = 1.2 nM), matching the predicted value and representing a 10-fold gain over compound 2. FEP+ also correctly forecast that the R-enantiomer (11) would be markedly more potent than the S-enantiomer (10) (~30-fold difference).

Fig. 3. SAR of Substitutions on the Dihydro-Pyrrole Ring

4. Core 1 Modification and the Discovery of Compound 26 (SGR-1505)

By introducing modest changes to the pyrazolopyrimidine Core 1 of compound 11 (e.g., F, Me) and evaluating potency with FEP+ while assessing ADME properties through MPO, the team identified compound 26 (SGR-1505, Fig. 4). It retained low-nanomolar activity (IC₅₀ = 1.3 nM), showed high metabolic stability (low hepatic microsomal CLint), excellent permeability (MDCK-MDR1 = 3.4 × 10⁻⁶ cm s⁻¹), and a markedly improved oral bioavailability (mouse F% = 32%, ~5-fold increase in AUC).

Fig. 4. Exploration of Substitutions on the Pyrazolopyrimidine Core

Preclinical Profiling of SGR-1505

Across pre-clinical studies SGR-1505 has demonstrated the attributes required of a best-in-class MALT1 inhibitor: sub-nanomolar potency (mean IC₅₀ = 1.3 nM; Fig. 5), no appreciable activity against a panel of 468 kinases or 17 proteases (Fig. 6), and robust blockade of NF-κB signalling and downstream cytokine release. Pharmacokinetic profiles are favourable in every species evaluated—low clearance, moderate-to-long half-life and moderate-high oral bioavailability. In two ABC-DLBCL mouse xenograft models, oral administration of SGR-1505 produced dose-dependent tumour growth inhibition and outright regressions; combination with ibrutinib yielded synergistic anti-tumour activity, and all doses were well tolerated (Fig. 7).

Fig. 5. In Vitro Pharmacological Profiling of SGR-1505

Fig. 6. Kinase selectivity of SGR-1505 (10 μM) was obtained from KINOMEscanTM (Eurofins, 468 kinases)

Fig. 7. SGR-1505 Inhibits Tumor Growth In Vivo

Conclusion

SGR-1505 is a potent, highly selective, and orally bioavailable allosteric MALT1 inhibitor that demonstrates robust in vitro and in vivo efficacy. Having entered clinical evaluation (NCT05544019), it holds promise as a new targeted therapy for patients with B-cell malignancies. Its discovery also validates the value of a free-energy–based, multiparameter drug-design platform in accelerating first-in-class drug discovery.

PRODUCT SUGGESTION

Synthesis of Compound 26

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SGR-1505 Intermediates

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Other Related Building Blocks

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