Design of the Firstâ inâ Class, Highly Potent Irreversible Inhibitor Targeting the Meninâ MLL Proteinâ Protein Interaction

The structureâ based design of Mâ 525 as the firstâ inâ class, highly potent, irreversible smallâ molecule inhibitor of the meninâ MLL interaction is presented. Mâ 525 targets cellular menin protein at subâ nanomolar concentrations and achieves low nanomolar potencies in cell growth inhibition and in the suppression of MLLâ regulated gene expression in MLL leukemia cells. Mâ 525 demonstrates high cellular specificity over nonâ MLL leukemia cells and is more than 30 times more potent than its corresponding reversible inhibitors. Mass spectrometric analysis and coâ crystal structure of Mâ 525 in complex with menin firmly establish its mode of action. A single administration of Mâ 525 effectively suppresses MLLâ regulated gene expression in tumor tissue. An efficient procedure was developed to synthesize Mâ 525. This study demonstrates that irreversible inhibition of menin may be a promising therapeutic strategy for MLL leukemia.Irreversible inhibitor Mâ 525 targets the meninâ MLL interaction. It is demonstrated that irreversible inhibition of menin is a promising therapeutic strategy for the treatment of MLL leukemia and may have advantages over reversible inhibitors.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141532/1/anie201711828.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141532/2/anie201711828-sup-0001-misc_information.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141532/3/anie201711828_am.pd

Design of the Firstâ inâ Class, Highly Potent Irreversible Inhibitor Targeting the Meninâ MLL Proteinâ Protein Interaction

The structureâ based design of Mâ 525 as the firstâ inâ class, highly potent, irreversible smallâ molecule inhibitor of the meninâ MLL interaction is presented. Mâ 525 targets cellular menin protein at subâ nanomolar concentrations and achieves low nanomolar potencies in cell growth inhibition and in the suppression of MLLâ regulated gene expression in MLL leukemia cells. Mâ 525 demonstrates high cellular specificity over nonâ MLL leukemia cells and is more than 30 times more potent than its corresponding reversible inhibitors. Mass spectrometric analysis and coâ crystal structure of Mâ 525 in complex with menin firmly establish its mode of action. A single administration of Mâ 525 effectively suppresses MLLâ regulated gene expression in tumor tissue. An efficient procedure was developed to synthesize Mâ 525. This study demonstrates that irreversible inhibition of menin may be a promising therapeutic strategy for MLL leukemia.Der irreversible Inhibitor Mâ 525 greift an der Meninâ MLLâ Wechselwirkung an. Die irreversible Inhibition von Menin erweist sich als vielversprechende Strategie für die Behandlung von MLLâ Leukämie, mit möglichen Vorteilen gegenüber dem Einsatz reversibler Inhibitoren.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141701/1/ange201711828_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141701/2/ange201711828.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141701/3/ange201711828-sup-0001-misc_information.pd

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Small Molecule Inhibitors of MDM2-p53 and MDMX-p53 Interactions as New Cancer Therapeutics

Inactivation of the function of tumor suppressor p53 is common in human cancers. In approximately half of human cancers, the tumor suppressor function of p53 is inactivated by deletion or mutation of TP53, the gene encoding p53 protein. In the remaining 50% of human cancers, p53 tumor suppressor function can be effectively inhibited by oncoprotein MDM2 or its homolog MDMX. Since inhibition of p53 by MDM2 or MDMX protein is mediated by their direct interaction with p53, small-molecule inhibitors designed to block the MDM2-p53 or MDMX-p53 protein-protein interaction (MDM2 or MDMX inhibitors) can activate p53 in tumor cells retaining wild-type p53. In the last few years, several classes of potent, selective, and efficacious small molecule MDM2 inhibitors have been designed and developed, and six such compounds are being evaluated in clinical trials as new anticancer drugs. Additionally, non-peptide, small-molecule MDMX inhibitors have been reported. We review herein the design and development of potent small-molecule MDM2 and MDMX inhibitors

Structure-Based Design of High-Affinity Macrocyclic Peptidomimetics to Block the Menin-Mixed Lineage Leukemia 1 (MLL1) Protein–Protein Interaction

Menin is an essential oncogenic cofactor for mixed lineage leukemia 1 (MLL1)-mediated leukemogenesis through its direct interaction with MLL1. Targeting the menin–MLL1 protein–protein interaction represents a promising strategy to block MLL1-mediated leukemogenesis. Employing a structure-based approach and starting from a linear MLL1 octapeptide, we have designed a class of potent macrocyclic peptidomimetic inhibitors of the menin–MLL1 interaction. The most potent macrocyclic peptidomimetic (MCP-1), <b>34</b>, binds to menin with a <i>K</i>_i value of 4.7 nM and is >600 times more potent than the corresponding acyclic peptide. Compound <b>34</b> is also less peptide-like and has a lower molecular weight than the initial MLL1 peptide. Therefore, compound <b>34</b> serves as a promising lead structure for the design of potent and cell-permeable inhibitors of the menin–MLL1 interaction

Design of Chemically Stable, Potent, and Efficacious MDM2 Inhibitors That Exploit the Retro-Mannich Ring-Opening-Cyclization Reaction Mechanism in Spiro-oxindoles

Inhibition of the MDM2–p53 protein–protein interaction is being actively pursued as a new anticancer therapeutic strategy, and spiro-oxindoles have been designed as a class of potent and efficacious small-molecule inhibitors of this interaction (MDM2 inhibitors). Our previous study showed that some of our first-generation spiro-oxindoles undergo a reversible ring-opening-cyclization reaction that, from a single compound in protic solution, results in an equilibrium mixture of four dia­stereo­isomers. By exploiting the ring-opening-cyclization reaction mechanism, we have designed and synthesized a series of second-generation spiro-oxindoles with symmetrical pyrrolidine C2 substitution. These compounds undergo a rapid and irreversible conversion to a single, stable dia­stereo­isomer. Our study has yielded compound <b>31</b> (MI-1061), which binds to MDM2 with <i>K</i>_i = 0.16 nM, shows excellent chemical stability, and achieves tumor regression in the SJSA-1 xenograft tumor model in mice

Design of Chemically Stable, Potent, and Efficacious MDM2 Inhibitors That Exploit the Retro-Mannich Ring-Opening-Cyclization Reaction Mechanism in Spiro-oxindoles

Inhibition of the MDM2–p53 protein–protein interaction is being actively pursued as a new anticancer therapeutic strategy, and spiro-oxindoles have been designed as a class of potent and efficacious small-molecule inhibitors of this interaction (MDM2 inhibitors). Our previous study showed that some of our first-generation spiro-oxindoles undergo a reversible ring-opening-cyclization reaction that, from a single compound in protic solution, results in an equilibrium mixture of four dia­stereo­isomers. By exploiting the ring-opening-cyclization reaction mechanism, we have designed and synthesized a series of second-generation spiro-oxindoles with symmetrical pyrrolidine C2 substitution. These compounds undergo a rapid and irreversible conversion to a single, stable dia­stereo­isomer. Our study has yielded compound <b>31</b> (MI-1061), which binds to MDM2 with <i>K</i>_i = 0.16 nM, shows excellent chemical stability, and achieves tumor regression in the SJSA-1 xenograft tumor model in mice