First-in-class of SHMT2 and MTHFD2 inhibitors as antitumor agents
Inventors
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Assignees
Wayne State University • Duquesne University of the Holy Spirit
Member
Nanomedicine Manufacturing Lab, Duquesne UniversityNANOMEDICINE MANUFACTURING LABORATORY
Nanomedicines produced at NML include colloidal nanosystems for molecular imaging (magnetic resonance imaging (MRI) and near-infrared fluorescence (NIRF) imaging), targeted and local drug delivery, and imaging-supported drug delivery and theranostic nanomedicines and biomaterials. These products can be delivered locally, parenterally, or implanted into body cavities or wounds. Nanotechnology-based therapeutics are typically presented with high costs and challenging quality control, representing critical barriers to future clinical translation. In contrast, the offeror NML efforts over the past decade produced cost-effective, robust, and scalable manufacturing methods for nanomedicines with a high level of quality control by utilizing Quality-by-Design (QbD) approaches. Specifically, the application of QbD to nanomedicine manufacturing and quality control led to several firsts: 1) the first imaging-supported pain nanomedicine for trauma and surgical pain; 2) the first oxygen carrier with embedded imaging agents for real-time in line tracking during organ/limb preservation; 3) the first successful longitudinal immunomonitoring in non-human primates and porcine models using clinical grade imagers; 4) demonstrated nerve injury recovery following trauma by local nanomedicine implantation in rodents. NML also designs and produces biocompatible and multi-drug delivery hydrogels and biomaterials for multitude of applications, from supporting neuroregeneration to local immunosuppression and wound healing. Furthermore, NML successfully scaled up their laboratory protocols to produce >2L of nanoparticles/batch and evaluate them in human limb trials for oxygen delivery. The work in these areas has been supported by USAF and CDMRP contracts, which are highly collaborative and involve partners across academia, industry and Government. NML is currently funded by CDMRP and ARPA H.
Founded in 1878, Duquesne University is consistently ranked among the nation's top Catholic universities for its award-winning faculty and horizon-expanding education. Research happens in all fields across the University, from the humanities and sciences to health-related fields and business. This research is supported by the federal and state governments, foundations, and corporate partners. Duquesne's Pittsburgh location connects researchers of all kinds to a knowledge economy powered by large tech, medical, energy, and industrial sectors.
NANOMEDICINE MANUFACTURING LABORATORY Nanomedicines produced at NML include colloidal nanosystems for molecular imaging (magnetic resonance imaging (MRI) and near-infrared fluorescence (NIRF) imaging), targeted and local drug delivery, and imaging-supported drug delivery and theranostic nanomedicines and biomaterials. These products can be delivered locally, parenterally, or implanted into body cavities or wounds. Nanotechnology-based therapeutics are typically presented with high costs and challenging quality control, representing critical barriers to future clinical translation. In contrast, the offeror NML efforts over the past decade produced cost-effective, robust, and scalable manufacturing methods for nanomedicines with a high level of quality control by utilizing Quality-by-Design (QbD) approaches. Specifically, the application of QbD to nanomedicine manufacturing and quality control led to several firsts: 1) the first imaging-supported pain nanomedicine for trauma and surgical pain; 2) the first oxygen carrier with embedded imaging agents for real-time in line tracking during organ/limb preservation; 3) the first successful longitudinal immunomonitoring in non-human primates and porcine models using clinical grade imagers; 4) demonstrated nerve injury recovery following trauma by local nanomedicine implantation in rodents. NML also designs and produces biocompatible and multi-drug delivery hydrogels and biomaterials for multitude of applications, from supporting neuroregeneration to local immunosuppression and wound healing. Furthermore, NML successfully scaled up their laboratory protocols to produce >2L of nanoparticles/batch and evaluate them in human limb trials for oxygen delivery. The work in these areas has been supported by USAF and CDMRP contracts, which are highly collaborative and involve partners across academia, industry and Government. NML is currently funded by CDMRP and ARPA H. Founded in 1878, Duquesne University is consistently ranked among the nation's top Catholic universities for its award-winning faculty and horizon-expanding education. Research happens in all fields across the University, from the humanities and sciences to health-related fields and business. This research is supported by the federal and state governments, foundations, and corporate partners. Duquesne's Pittsburgh location connects researchers of all kinds to a knowledge economy powered by large tech, medical, energy, and industrial sectors.
Publication Number
US-11384084-B2
Publication Date
2022-07-12
Expiration Date
2038-08-30
Abstract
A compound of the Formula I and optionally a pharmaceutically acceptable salt thereof is provided: Formula I, wherein, R is one selected from the group consisting of H and CH3; n is an integer 4 when X is —CH2— and Ar is 1,4-phenyl, or n is an integer ranging from 1 to 4 when X is —CH2— and Ar is either 2′-fluoro-1,4-phenyl or 2,5-thienyl, or n is an integer ranging from 1 to 4 when X is one selected from the group consisting of O, S, —NH—, —NHCHO—, —NHCOCH3—, and —NHCOCF3— and Ar is one selected from the group consisting of (a) 1,4-phenyl, (b) 2′-fluoro-1,4-phenyl, and (c) 2,5-thienyl, or n is an integer 3 when X is —CH2—, R is CH3 and Ar is 1,4-phenyl.
Core Innovation
The invention relates to novel compounds of Formulae I, II, and III, and their pharmaceutically acceptable salts, which are effective inhibitors of human tumor cells, particularly lung and pancreatic cancer cells. These compounds act as inhibitors of serine hydroxymethyltransferase 2 (SHMT2) and 5,10-methylene tetrahydrofolate dehydrogenase 2 (MTHFD2), which are enzymes critical to mitochondrial one-carbon metabolism. The invention also covers pharmaceutical compositions containing these compounds and their use in treating cancer.
There is a recognized need to develop inhibitors targeting SHMT2 and MTHFD2, as no known inhibitors exist for either enzyme. SHMT2 has been identified as an oncodriver in various cancers, and its inhibition, as demonstrated through knockouts, leads to glycine auxotrophy in tumor cells—an exploitable vulnerability. The lack of effective SHMT2 or MTHFD2 inhibitors for clinical use underlines the problem addressed by this invention.
The core innovation is the discovery of first-in-class small-molecule inhibitors with potent activity against human tumor cells by targeting SHMT2/MTHFD2 and interfering with mitochondrial one-carbon metabolism. These inhibitors, structurally defined as 5-substituted pyrrolo[3,2-d]pyrimidine analogs and related structures, not only affect mitochondrial metabolism but also target cytosolic pathways involved in purine and thymidylate biosynthesis, providing broad-spectrum antitumor activity and overcoming resistance to current chemotherapies.
Claims Coverage
The patent presents several inventive features through its independent claims, primarily centered around novel compounds, pharmaceutical compositions, and therapeutic methods related to SHMT2 and MTHFD2 inhibition.
Compound of Formula I with antitumor activity
A compound represented by Formula I, and optionally a pharmaceutically acceptable salt thereof, wherein R is selected from H and CH3; n is an integer ranging from 1 to 4; X is selected from —CH2—, O, S, —NH—, —NHCHO—, —NHCOCH3—, and —NHCOCF3—; and Ar is selected from 1,4-phenyl, 2'-fluoro-1,4-phenyl, and 2,5-thienyl. This structural feature provides the basis for specific SHMT2 and/or MTHFD2 inhibition and antitumor effects.
Pharmaceutical composition comprising a compound of Formula I
A pharmaceutical composition containing a therapeutically effective amount of a compound of Formula I, and optionally a pharmaceutically acceptable salt thereof, wherein the compound is as described above, and the composition comprises a pharmaceutically acceptable carrier. This covers pharmaceutical preparations suitable for cancer therapy using the claimed compounds.
The independent claims of the patent provide coverage for novel chemical entities of Formula I and their pharmaceutical compositions, specifically as inhibitors of SHMT2 and/or MTHFD2 for cancer treatment.
Stated Advantages
The compounds are first-in-class inhibitors of SHMT2 and/or MTHFD2, targeting a previously unaddressed metabolic vulnerability in cancer cells.
They demonstrate potent inhibition of human tumor cells, including resistance-overcoming activity in lung and pancreatic cancer models.
The compounds show in vivo antitumor efficacy in animal models, with better anti-tumor efficacy compared to the standard-of-care agent gemcitabine at significantly lower doses.
These inhibitors target both mitochondrial and cytosolic one-carbon metabolism, offering broad-spectrum antitumor activity.
Documented Applications
Treatment of cancer, including specific use against tumors such as lung cancer and pancreatic cancer.
Use as pharmaceutical compositions for administration to cancer patients to inhibit tumor cell growth or treat malignancies.
Methods for targeting mitochondrial metabolism, particularly by administering effective amounts of compounds to cancer patients.
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