PI3K inhibitors and uses thereof
Inventors
Fushimi, Makoto • SCALTRITI, Maurizio • Heller, Daniel Alan • Monterrubio Martinez, Carles • Arruabarrena Aristorena, Amaia • Meinke, Peter T. • Foley, Michael Andrew • Asano, Yasutomi • Aso, Kazuyoshi • TAKAHAGI, Hiroki • SHAMAY, Yosef • Baselga Torres, Jose Manuel • Sasaki, Yusuke • MICHINO, Mayako
Assignees
Memorial Sloan Kettering Cancer Center • Tri Institutional Therapeutics Discovery Institute Inc
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Publication Number
US-12478616-B2
Publication Date
2025-11-25
Expiration Date
Abstract
The development of a new, targeted drug delivery paradigm coupled to improved PI3K inhibitors (e.g., PI3Kα inhibitors) represents a significant advance in cancer therapy. Provided herein are compounds, such as compounds of Formula (I) and (II), and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof. The compounds provided herein are PI3K (e.g., PI3Kα) inhibitors and are therefore useful for the treatment and/or prevention of various diseases (e.g., proliferative diseases such as cancer). Also provided herein are nanoparticles and nanogels (e.g., P-selectin targeting nanoparticles) comprising PI3K inhibitors, such a compound described herein. In certain embodiments, a nanoparticle or nanogel described herein encapsulates a compound described herein for targeting delivery to cancer cells or tumors.
Core Innovation
The invention provides compounds of Formula (I) and Formula (II), or pharmaceutically acceptable salts thereof, defined by variable substituents R1, R2, R3, R4, R5, and R6, together with nitrogen substituents RN1, RN2, and RN, oxygen substituents RO and RO2, sulfur substituents RS, and index constraints on p, n, and m. The substituent sets include hydrogen, halogen, cyano, azide, nitro, optionally substituted alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, acyl, and protecting-group embodiments, with additional conditions for Formula (II) including R6, R7, and R8 restrictions.
The compounds are positioned as PI3Kα inhibitor compounds for therapeutic use in proliferative diseases associated with PI3Kα. The disclosure also describes derivative forms including prodrug, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, and isotopically labeled derivative forms.
A targeted delivery concept is described using P-selectin-targeting nanoparticles or nanogels, including fucoidan or sulfated polymer-based targeting, to encapsulate the PI3K inhibitors. This targeting is intended to increase tumor localization and improve therapeutic index while reducing systemic toxicity.
Therapeutic use is documented across PI3Kα-associated cancers and proliferative diseases, including head and neck squamous cell carcinoma (HNSCC), glioblastoma, breast cancer, ovarian cancer, cervical cancer, lung cancer, kidney cancer, bladder cancer, liver cancer, sarcoma, leukemias, lymphomas, and myelomas.
Claims Coverage
The provided claim material identifies two independent formula-based compound claims, Formula (I) and Formula (II), each covering pharmaceutically acceptable salts and broad substituent-variable frameworks. The coverage is primarily structural, with dependent refinements that specify substituent choices and conditional R6/R7/R8 limitations.
Formula (I) compound with defined substituent framework
A compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, RN1, RN2, RN, RO, RO2, RS, and indices p, n, and m are defined by the recited options and integer constraints.
Formula (II) compound with defined substituent framework and conditional limitations
A compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein R1, R3, R4, R5, RN1, RN2, RN, RO, RS, n, m, p, R6, R7, and R8 are defined by the recited options, with additional conditions when R6 is —CF3 requiring at least one of R7 or R8 to be not hydrogen.
Selected compound structures from an enumerated group
The compound of Formula (II) is selected from a group consisting of specified alternative chemical structures, together with pharmaceutically acceptable salts thereof.
Pharmaceutical composition with pharmaceutically acceptable excipient
A pharmaceutical composition that includes a claimed compound or pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable excipient.
In vitro PI3Kα enzymatic inhibition using an effective amount
A method for inhibiting PI3Kα enzymatic activity in vitro by contacting a PI3Kα enzyme with an effective amount of a claimed compound, salt, or pharmaceutical composition thereof.
Overall, the claim coverage centers on Formula (I) and Formula (II) compound scaffolds with broad substituent variation and discrete index ranges, together with conditional narrowing in Formula (II), selected compound structures, pharmaceutical compositions, and in vitro PI3Kα enzymatic inhibition.
Stated Advantages
The disclosure states that Compound 22 and Compound 18 have permeability and distinct microsomal lability (mouse versus human).
The carboxylic acid Compound 19 is stable in microsomes but clears rapidly in vivo.
Compounds 19, 18, and 22 are successfully encapsulated into fucoidan polysaccharide nanoparticles with measured drug loading.
Fucoidan-based P-selectin-targeted nanoparticles are described as showing selective binding to P-selectin versus L-selectin, E-selectin, and BSA.
The disclosure reports penetration and efficacy evaluations, including penetration into tumor spheroids and associated measurements of pathway-related activity and apoptosis markers.
Improved therapeutic index.
Increased tumor localization.
Reduced systemic toxicity.
Tumor-specific PI3K pathway suppression, including S6 phosphorylation and cleaved caspase-3.
Enhanced therapeutic effect with radiation.
Reduced systemic hyperglycemia and insulinemia.
Improved survival with less drug burden.
Documented Applications
Inhibiting PI3Kα enzymatic activity in vitro by contacting a PI3Kα enzyme with an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof.
Fucoidan-based nanoparticle delivery, including FiPAX, FiMEK, and FiDOX.
Radiation-guided P-selectin induction and evaluation of nanoparticle delivery in that context.
MEK162 nanoparticle delivery.
Penetration into tumor spheroids.
Treating proliferative diseases associated with PI3Kα, including head and neck squamous cell carcinoma (HNSCC), glioblastoma, breast cancer, ovarian cancer, cervical cancer, lung cancer, kidney cancer, bladder cancer, liver cancer, sarcoma, leukemias, lymphomas, and myelomas.
P-selectin-targeted nanoparticle or nanogel delivery of PI3Kα inhibitors, including fucoidan or sulfated polymer-based targeting.
In vitro inhibition of PI3Kα enzymatic activity.
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