Sri International

La Jolla Cancer Research Foundation

The United States Government as Represented by the Department of Veterans Affairs

Wayne State University

Oregon State University

Sanford-Burnham Medical Research Institute

The Burnham Institute

Molecular Medicine Research Institute

Peter D Hobbs

Masato Tanabe

Wan-Ru Chao

Marcia I Dawson

Magnus Pfahl

Richard H Peters

Ling Jong

Xiao-kun Zhang

Jurgen M Lehmann

Rebecca L Chan

Marcia L Dawson

Keith R Laderoute

Joseph A Fontana

Mark Leid

J Urgen Lehmann

Marcia Dawson

Krzysztof A Derdzinski

Xiao-Kun Zhang

Joy M Calaoagan

Khalid Amin

The present invention provides compounds that are inducers or inhibitors of apoptosis of apoptosis preceded by cell-cycle arrest. In addition, the present invention provides pharmaceutical compositions and methods for treating mammals with leukemia or other forms of cancer or for treating disease conditions caused by apoptosis of cells.

Induction of apoptosis in cancer cells

The present invention provides compounds that are inducers or inhibitors of apoptosis or apoptosis preceded by cell-cycle arrest. In addition, the present invention provides pharmaceutical compositions and methods for treating mammals with leukemia or other forms of cancer or for treating disease conditions caused by apoptosis of cells.

Bridged bicyclic aromatic compounds are provided having the structure ##STR1## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and n are as defined herein. The novel compounds are useful for modulating gene expression of retinoic acid receptors, vitamin D receptors and thyroid receptors. Pharmaceutical compositions and methods for modulating gene expression are provided as well.

Bridged bicyclic aromatic compounds and their use in modulating gene

The invention provides a method of screening a substance for the ability to effect the formation of a retinoid X receptor homodimer comprising combining the substance and a solution containing retinoid X receptors and determining the presence of homodimer formation. Also provided is a method of screening a substance for an effect on a retinoid X receptor homodimer's ability to bind DNA comprising combining the substance with the homodimer and determining the effect of the compound on the homodimer's ability to bind DNA. A method of inhibiting an activity of a retinoid X receptor heterodimer comprising increasing the formation of a retinoid X receptor homodimer, thereby preventing the retinoid X receptor from forming a heterodimer and preventing the resulting heterodimer activity is also provided. A method of inhibiting an activity of a retinoid X receptor homodimer is also provided. A method of determining an increased probability of a pathology associated with retinoid X receptor homodimer formation and treating such pathology are further provided. In addition, a method of screening a response element for binding with a retinoid X receptor homodimer is provided. Finally, the invention provides methods of activating retinoid X receptor homodimer formation.

RXR homodimer formation

The invention provides a method of screening a substance for the ability to effect the formation of a retinoid X receptor homodimer comprising combining the substance and a solution containing retinoid X receptors and determining the presence of homodimer formation. Also provided is a method of screening a substance for an effect on a retinoid X receptor homodimer's ability to bind DNA comprising combining the substance with the homodimer and determining the effect of the compound on the homodimer's ability to bind DNA. A method of inhibiting an activity of a retinoid X receptor heterodimer comprising increasing the formation of a retinoid X receptor homodimer, thereby preventing the retinoid X receptor from forming a heterodimer and preventing the resulting heterodimer activity is also provided. A method of inhibiting an activity of a retinoid X receptor homodimer is also provided. In addition, a method of screening a response element for binding with a retinoid X receptor homodimer is provided. Finally, the invention provides methods of activating retinoid X receptor homodimer formation.

Aromatic retinoic acid analogues of the formula ##STR1## where X is hydrogen or fluorine, Y is hydrogen, halogen of atomic number 9 or 17, hydroxy, alkyl of 1 to 2 carbon atoms or alkoxy of 1 to 2 carbon atoms and R is hydroxy, alkoxy, aroxy, or NR.sup.1 R.sup.2 where R.sup.1 is hydrogen, alkyl, or aryl and R.sup.2 is alkyl or aryl, with the proviso that when Y is hydrogen, X is fluorine. These retinoids are useful as chemopreventive agents for inhibiting tumor promotion in epithelial cells and for treating nonmalignant skin disorders.

Aromatic retinoic acid analogues

Retinoic acid-4,4,18,18,18-d.sub.5 and esters and amides thereof are disclosed. These compounds are useful as chemopreventive agents for inhibiting tumor promotion in epithelial cells and for treating nonmalignant skin disorders.

Pentadeuterioretinoids

A compound of the formula: ##STR1## where X is ##STR2## and R is hydroxy, or an alkoxy with 0 or 1 hydroxy substituent, or aroxy with 0 or 1 hydroxy substituent, or alkoxy monosubstituted phenoxy, or NR.sup.1 R.sup.2 where R.sup.1 is hydrogen, or an alkyl or aryl with 0 or 1 hydroxy substituent, and R.sup.2 is an alkyl or aryl with 0 or 1 hydroxy substituent. These compounds are useful as chemopreventive agents for inhibiting tumor promotion in ephithelial cells and for treating nonmalignant skin disorders.

N-heterocyclic retinoic acid analogues

Compounds of the formulas: ##STR1## where X is methyl, methoxy, chlorine, or hydrogen, Y and Y.sub.1 are fluorine or hydrogen, R is hydroxy, alkoxy with 0 or 1 hydroxy substituent, aroxy, or NR.sup.1 R.sup.2 where R.sup.1 is hydrogen, alkyl with 0 or 1 hydroxy substituent or aryl and R.sup.2 is alkyl with 0 or 1 hydroxy substituent or aryl with the proviso that when Y or Y.sup.1 is fluorine, the other Y or Y.sup.1 is hydrogen. These compounds are useful as chemopreventive agents for inhibiting tumor promotion in epithelial cells and for treating nonmalignant skin disorders.

Naphthyl or tetrahydronaphthyl-substituted naphthoic acid and derivatives

5,6-Methano-5,6-dihydroretinoids such as ethyl (E)-5,6-methano-5,6-dihydroretinoate and (E)-1-(4-carbethoxyphenyl)-2-methyl-4-(2,2,6-trimethylbicyclo[4.1.0]hept-1 -yl)-1,3-butadiene are disclosed. These componds are useful as chemopreventive agents for inhibiting tumor promotion in epithelial cells and for treating nonmalignant skin disorders.

Growing community of inventors

Moss Beach, CA, United States of America

Peter D Hobbs