Treatment of neurofibromatosis with radicicol and its derivatives
Inventors
Chen, Ruihong • Rubenstein, Allan E. • Yu, Jin-Chen • Winssinger, Nicolas • Barluenga, Sofia
Assignees
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Publication Number
US-8329683-B2
Publication Date
2012-12-11
Expiration Date
Abstract
The present invention provides compounds of formulae Ia, Ia′, IIa, IIa′, IIIa, IIIa′, IVa, or Va and the therapeutic use thereof. The present invention also includes methods of treating NF2-deficient or NF1-deficient cells or neurodegenerative diseases with radicicol or its derivatives, such as one or more compounds of formula I, II, III, IV, V, Ia, Ia′, IIa, IIa′, IIIa, IIIa′, IVa, or Va. Furthermore, the present invention is directed to methods of inhibiting the growth of NF2-deficient or NF1-deficient tumors. The methods comprise contacting NF2-deficient or NF1-deficient tumor cells with radicicol or its derivatives, such as one or more compounds of formula I, II, III, IV, V, Ia, Ia′, IIa, IIa′, IIIa, IIIa′, IVa, or Va. The present invention is also directed to the combinational use of radicicol or its derivatives, such as one or more compounds of formula I, II, III, IV, V, Ia, Ia′, IIa, IIa′, IIIa, IIIa′, IVa, or Va with at least one additional active agent, such as one or more HSP90 inhibitors.
Core Innovation
The invention provides a method of inhibiting or reducing the growth or number of NF2-deficient tumor cells or NF1-deficient tumor cells by contacting the tumor cells with at least one compound of formula I or I932, or a tautomer thereof, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof. The compounds are defined by structural variables X and Y, where X is O, S or NR and Y is selected from OR, O(CH2)mCOOR, O(CH2)mCON(R)2, N(R)2, N(R)SOR or N(R)SO2R, and the groups bound to the nitrogen atom may be in Z- or E-configuration.
The scope further includes multiple independently selectable substituents R1, R2, R3 through R10, each R, and an inorganic or organic counterion Z, together with parameters n, m and p. In formula I932, when n is 1 and X is O, additional conditional constraints apply depending on whether the bond between the carbon atoms bearing R9 and R10 is a double bond or a single bond, and at least one of specified substituents is not hydrogen.
The disclosed subject matter is described with radicicol and resorcylic-acid lactone derivative language, and with formula I or I932 embodiments used for inhibiting or reducing the growth or number of NF2-deficient tumor cells or NF1-deficient tumor cells. The document also ties the method to HSP90 function reduction and/or HSP70 increase, and describes selected tumor types and cancer cell sources within the NF2-deficient and NF1-deficient context.
Claims Coverage
The consolidated claim coverage centers on the independent method claim for contacting NF2-deficient or NF1-deficient tumor cells with compounds of formula I or I932 (including tautomer, salt, solvate, ester and prodrug forms). The provided set supports four inventive features: the contacting method itself, the defined X/Y and substituent framework for the compounds, the broad substituent definitions, and the conditional non-hydrogen substituent requirements in formula I932.
Contacting NF2-deficient or NF1-deficient tumor cells with formula I or I932 compounds
A method of inhibiting or reducing the growth or number of NF2-deficient tumor cells or NF1-deficient tumor cells by contacting the tumor cells with at least one compound of formula I or I932, or a tautomer thereof, a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
Defined formula I/I932 scaffold with X and Y group selections
The compounds are defined such that X is O, S or NR, and Y is selected from OR, O(CH2)mCOOR, O(CH2)mCON(R)2, N(R)2, N(R)SOR or N(R)SO2R, with nitrogen-bound groups optionally in Z- or E-configuration.
Broad substituent definitions for R1, R2, R3 through R10, R and Z
R1, R2 and R3 through R10 are independently selected from the recited substituent groups, each R may be optionally substituted, and Z is an inorganic or organic counterion, with the formula also using parameters n, m and p.
Conditional non-hydrogen substituent requirement in formula I932
In formula I932, when n is 1 and X is O, and depending on whether the bond between the carbon atoms bearing R9 and R10 is a double bond or a single bond, at least one of the specified substituents is not hydrogen.
The claim coverage is anchored on the method of contacting NF2-deficient or NF1-deficient tumor cells with formula I or I932 compounds and their defined forms, with the inventive chemical scope set by the X/Y framework, broad substituent definitions, and conditional non-hydrogen substituent restrictions in formula I932.
Stated Advantages
Inhibiting or reducing the growth or number of NF2-deficient tumor cells.
Inhibiting or reducing the growth or number of NF1-deficient tumor cells.
Reducing HSP90 function and/or increasing HSP70.
Documented Applications
A method for inhibiting or reducing the growth or number of NF2-deficient tumor cells or NF1-deficient tumor cells by contacting them with compounds of formula I or I932.
Use in NF2-deficient and NF1-deficient tumor cell contexts, including selected tumor types and cancer cell sources.
Use associated with HSP90 function reduction and/or HSP70 increase.
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