Bryostatin compounds and methods of preparing the same
Inventors
Wender, Paul • Quiroz, Ryan • Ho, Stephen • Shimizu, Akira • Ryckbosch, Steven • Stevens, Matthew C. • Jeffreys, Matthew S. • Hardman, Clayton • Sloane, Jack
Assignees
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Publication Number
US-12435071-B2
Publication Date
2025-10-07
Expiration Date
Abstract
Methods for preparing a variety of bryostatin compounds are provided. The subject methods provide for preparation of bryostatin 1 in multi-gram quantities in a low and unprecedented number of convergent synthetic steps from commercially available materials. The subject methods are scalable with low estimated material costs and can provide enough material to meet clinical needs. Also provided are a variety of bryostatin analog compounds, and prodrug forms thereof, which are synthetically accessible via the subject methods and pharmaceutical compositions including the same.
Core Innovation
The invention relates to methods of treating cancer by administering a therapeutically effective amount of a pharmaceutical composition comprising a bryostatin analog and a pharmaceutically acceptable vehicle to an individual in need thereof. The bryostatin analog is defined by specific chemical formulas and variable substitution patterns, including optional solvate, hydrate, prodrug, or salt forms.
The bryostatin analog includes defined groups W1, Z2, R5, R6, R7, R8, X1, X4, X5, Y1, R11, R12, R13, R16, and hydroxyl protecting group or promoiety options for R14 and R15. The definition also distinguishes cases depending on whether a covalent bond designated “b” is a double bond or a single bond, with corresponding allowed values for Z2.
The treated cancers are specified as melanoma, myeloma, chronic lymphocytic leukemia (CLL), AIDS-related lymphoma, non-Hodgkin’s lymphoma, colorectal cancer, renal cancer, prostate cancer, cancers of the head, neck, stomach, esophagus, anus, cervix, ovarian cancer, breast cancer, peritoneal cancer, and non-small cell lung cancer.
Claims Coverage
The claim set includes two independent claims directed to cancer treatment by administering a pharmaceutical composition containing a bryostatin analog with a specified structural formula and variable substitution definitions. The inventive features center on the administration method and the structural formula constraints for the bryostatin analog, including optional solvate, hydrate, prodrug, or salt forms.
Cancer treatment by administering defined bryostatin analogs
Administering a therapeutically effective amount of a pharmaceutical composition comprising a bryostatin analog and a pharmaceutically acceptable vehicle to an individual in need thereof, wherein the bryostatin analog has the formula (XXXIV) with defined W1, Z2, substituent groups (R5, R6, R7, R8, X1, X4, X5, Y1, R11, R12, R13, R16) and options for R14 and R15 as H, a hydroxyl protecting group, or a promoiety, with optional solvate, hydrate, prodrug form and/or salt thereof.
Cancer treatment by administering defined bryostatin analogs with alternative formula
Administering a therapeutically effective amount of a pharmaceutical composition comprising a bryostatin analog and a pharmaceutically acceptable vehicle to an individual in need thereof, wherein the bryostatin analog has the formula (XXXIII) with defined W1, X1, X2 and X3, Y1=OMe, and R12, R13, R16 substituent options, with R14 and R15 independently selected as H, a hydroxyl protecting group, or a promoiety, and optionally present as a solvate, hydrate or prodrug form and/or a salt thereof.
Overall, the independent claims cover administering a therapeutically effective amount of a pharmaceutical composition containing a bryostatin analog to treat cancer, with each claim grounded in a specific bryostatin-analog structural formula (XXXIV or XXXIII) and tightly defined substituent and covalent-bond variable options, including optional solvate/hydrate/prodrug/salt forms.
Stated Advantages
Enables clinical-scale supply of bryostatin 1.
Provides scalable multi-gram preparation.
Uses reduced-step convergent synthesis from commercially available materials.
Documented Applications
Treating cancer by administering bryostatin analog pharmaceutical compositions to an individual in need thereof.
PKC (CI-domain) modulation through binding to the PKC CI domain and modulation of CI-domain containing proteins, including PKC isoform selectivity.
Therapeutic use described for HIV/AIDS latency reversal, Alzheimer’s disease, neurodegenerative orphan diseases, stroke, and immune strengthening.
Combination therapy and synergy are stated as potential therapeutic approaches.
Scalable total synthesis approach for bryostatin and analog libraries is stated.
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