RELATED APPLICATIONS

This application claims priority from International Patent Application No. PCT/US2017/033182 filed May 17, 2017. The entire disclosures of which are incorporated herein by this reference.

BACKGROUND

Ras is one of the most highly validated targets for cancer drug discovery; however, the discovery of potent inhibitors of Ras has been difficult due to a lack of suitable binding pockets on the surface of Ras. The present inventors have discovered a binding pocket on the SOS protein, as part of the trimeric Ras:SOS:Ras complex and dimeric Ras:SOS complex, and small molecules that bind to this pocket and alter Ras activity in biochemical and cell-based experiments. These compounds are useful for treating cancer.

Without being bound by theory or mechanism, the Ras family of small GTPases function as molecular switches, cycling between inactive (GDP-bound) and active (GTP-bound) states to relay cellular signals in response to extracellular stimuli. The activation of Ras is tightly regulated by guanine nucleotide exchange factors (GEFs), such as Son of Sevenless (SOS), which catalyze nucleotide exchange, and GTPase-activating proteins (GAPs), which aid in GTP hydrolysis. Upon activation, GTP-bound Ras exerts its functions through protein-protein interactions with effectors such as Raf kinase and phosphoinositide 3-kinase to promote cell growth and survival.

Aberrant activation of Ras by increased upstream signaling, loss of GAP function, or oncogenic mutation results in the deregulation of cellular signals in cancer. Indeed, aberrant Ras signaling plays a role in up to 30% of all human cancers, with the highest incidence of Ras mutations occurring in carcinomas of the pancreas (63-90%), colon (36-50%), and lung (19-30%). Active Ras endows cells with capabilities that represent many of the hallmarks of cancer, including the ability to proliferate, evade programmed cell death, alter metabolism, induce angiogenesis, increase invasion and metastasis, and evade immune destruction. Importantly, inactivation of oncogenic Ras has been shown to be a promising therapeutic strategy in in vitro and in vivo models of cancer.

Embodiments of the present invention include compounds that increase the rate of SOS-mediated nucleotide exchange on Ras by binding to a functionally relevant, chemically tractable pocket on the SOS protein, as part of the Ras:SOS:Ras complex. High resolution X-ray co-crystal structures reveal the location of the binding pocket in the CDC25 domain near the catalytic site of SOS, adjacent to the Switch II region of Ras, and provide a detailed understanding of protein-ligand interactions. Mutational analyses confirmed the functional relevance of this binding site and showed it to be essential for compound activity. Perturbation of Ras signaling in HeLa and other cancer cells with these molecules demonstrates their ability to alter Ras activity in the setting of full-length proteins as well as cause cell death. The present invention is a new approach for targeting Ras signaling and provides compounds can be used to treat Ras-driven tumors.

Early attempts to inhibit Ras-driven tumors have focused on disrupting the posttranslational modification and localization of Ras or inhibiting Ras effectors. In contrast, embodiments of the present invention include compounds that activate nucleotide exchange by binding to a hydrophobic pocket on the SOS protein, as part of the Ras:SOS:Ras complex. Further, these compounds perturb Ras signaling in cancer cells and kill cancer cells. This discovery represents a new approach to alter Ras activity, and the compounds reported here may serve as starting points for the discovery of more optimized compounds that target Ras-mediated signaling.

Compound-mediated activation of SOS-catalyzed nucleotide exchange of the present invention is novel compared to previously reported mechanisms that increase nucleotide exchange. Mechanisms involving chelation of the divalent magnesium ion, destabilization of bound nucleotide, or activation via the allosteric Ras binding site on SOS were inconsistent with the results obtained in in vitro nucleotide exchange assays. In contrast, the present inventors discovered compounds of the present invention that increase nucleotide exchange by binding to a hydrophobic pocket on the SOS protein, as part of the Ras:SOS:Ras ternary complex.

Based on in vitro biochemical studies, the present inventors discovered that treatment of cells with compounds of the present invention resulted in diverse set of cellular responses. Indeed, Ras-GTP levels increased following the treatment of HeLa and other cancer cells with the compounds of the present invention, consistent with the observed increase in nucleotide exchange activity. Treatment of HeLa and other cancer cells would result in an increase of in downstream MAPK pathway signaling at low doses, but a decrease in MAPK signaling at higher doses. Further, downstream PI3K pathway signaling decreases in a dose-responsive manner. The present inventors thus discovered that rapid SOS-mediated activation of Ras, in the absence of other cooperative signal inputs, perturbs both MAPK and PI3K signaling.

SUMMARY

In accordance with the purpose(s) of the invention, as embodied and broadly described herein, the invention, in one aspect, relates to compounds useful as modulators of Ras activity, methods of making same, pharmaceutical compositions comprising same, and methods of treating cancer associated with alterations in Ras activity. Further disclosed are methods and pharmaceutical compositions useful for treating a disease related to Ras activity. In one aspect, the disclosed compounds can affect the efficiency at which SOS can activate Ras. The disclosed compounds can also affect the activity of the Ras:SOS:Ras ternary complex. The modulator of Ras activity can offer advantages over a molecule that blocks the GTP/GDP or SOS binding pockets, since basal signaling would not be inhibited.

Disclosed are compounds of the following formula:



wherein

X1is selected from C1-6—RA;

X2is selected from C1-6—RB;

RAis optionally substituted with one or more Z, and selected from H, alkyl, alkyl-amino, amino, amine, cyano, —OH, alkyl-OH, N—(CH2)1-6—OH, acetamidine, guanidine, N-containing cycloheteroalkyl, N-containing heteroaryl, amino-substituted cycloalkyl, amino-substituted heterocycloalkyl, amino-substituted aryl, halogen, cycloalkyl, heterocycloalkyl, heteroalkenyl, aminocycloalkyl, aminocycloalkenyl;

RBis optionally substituted with one or more Z and selected from H, alkyl, aminoalkyl, cycloalkyl, alkoxy, halogen, cycloheteroalkyl, aryl, heteroaryl,

R1is optionally substituted with one or more Z and selected from alkyl, benzyl, phenyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, alkyl-cycloalkyl, alkyl-aryl, alkyl-heteroaryl, alkenyl-cycloalkyl;

R2is optionally substituted with one or more Z, and selected from phenyl, benzyl, aryl, heteroaryl, alkyl-heteroalkyl, alkyl-heteroaryl, alkyl-cycloalkyl, biaryl, heterobiaryl, alkyl-biaryl, alkenyl, furanyl, thiophenyl, triazolyl, imidazolyl, pyrrolidinyl, thiazolyl, or forms a heteroalkyl ring with itself;

Z is independently H, alkyl, halogen, CF3, alkoxy, alkyl-alkoxy, OH, O—CF3, O-Me, acetonitrile, Cl, F, Br, cyano, CF3, or alkyl, including methyl, ethyl, vinyl, cyclopropyl, or more than one Z joins together to form a 5 or six membered ring;

or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof; provided that when X1is C—H, X2is CH, and R1is furan, R2is not phenyl and where X1is C—H, X2is CH, and R1is benzyl, R2is not phenyl.

Also disclosed are methods for enhancing SOS mediated nucleotide exchange on Ras in a subject comprising the step of administering to the subject at least one compound having a structure represented by a compound of the following formula:



wherein

X1is selected from C1-6—RA;

X2is selected from C1-6—RB;

RAis optionally substituted with one or more Z, and selected from H, alkyl, alkyl-amino, amino, amine, cyano, —OH, alkyl-OH, N—(CH2)1-6—OH, acetamidine, guanidine, N-containing cycloheteroalkyl, N-containing heteroaryl, amino-substituted cycloalkyl, amino-substituted heterocycloalkyl, amino-substituted aryl, halogen, cycloalkyl, heterocycloalkyl, heteroalkenyl, aminocycloalkyl, aminocycloalkenyl;

RBis optionally substituted with one or more Z and selected from H, alkyl, aminoalkyl, cycloalkyl, alkoxy, halogen, cycloheteroalkyl, aryl, heteroaryl,

R1is optionally substituted with one or more Z and selected from alkyl, benzyl, phenyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, alkyl-cycloalkyl, alkyl-aryl, alkyl-heteroaryl, alkenyl-cycloalkyl;

R2is optionally substituted with one or more Z, and selected from phenyl, benzyl, aryl, heteroaryl, alkyl-heteroalkyl, alkyl-heteroaryl, alkyl-cycloalkyl, biaryl, heterobiaryl, alkyl-biaryl, alkenyl, furanyl, thiophenyl, triazolyl, imidazolyl, pyrrolidinyl, thiazolyl, or forms a heteroalkyl ring with itself;

Z is independently H, alkyl, halogen, CF3, alkoxy, alkyl-alkoxy, OH, O—CF3, O-Me, acetonitrile, Cl, F, Br, cyano, CF3, or alkyl, including methyl, ethyl, vinyl, cyclopropyl, or more than one Z joins together to form a 5 or six membered ring;

or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof; in a dosage and amount effective to modulate Ras signaling in the subject.

Also disclosed are methods for modulating Ras signaling in at least one cell comprising the step of contacting at least one cell with at least one compound having a structure represented by a compound of the following formula:



wherein

X1is selected from C1-6—RA;

X2is selected from C1-6—RB;

RAis optionally substituted with one or more Z, and selected from H, alkyl, alkyl-amino, amino, amine, cyano, —OH, alkyl-OH, N—(CH2)1-6—OH, acetamidine, guanidine, N-containing cycloheteroalkyl, N-containing heteroaryl, amino-substituted cycloalkyl, amino-substituted heterocycloalkyl, amino-substituted aryl, halogen, cycloalkyl, heterocycloalkyl, heteroalkenyl, aminocycloalkyl, aminocycloalkenyl;

RBis optionally substituted with one or more Z and selected from H, alkyl, aminoalkyl, cycloalkyl, alkoxy, halogen, cycloheteroalkyl, aryl, heteroaryl,

R1is optionally substituted with one or more Z and selected from alkyl, benzyl, phenyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, alkyl-cycloalkyl, alkyl-aryl, alkyl-heteroaryl, alkenyl-cycloalkyl;

R2is optionally substituted with one or more Z, and selected from phenyl, benzyl, aryl, heteroaryl, alkyl-heteroalkyl, alkyl-heteroaryl, alkyl-cycloalkyl, biaryl, heterobiaryl, alkyl-biaryl, alkenyl, furanyl, thiophenyl, triazolyl, imidazolyl, pyrrolidinyl, thiazolyl, or forms a heteroalkyl ring with itself;

Z is independently H, alkyl, halogen, CF3, alkoxy, alkyl-alkoxy, OH, O—CF3, O-Me, acetonitrile, Cl, F, Br, cyano, CF3, or alkyl, including methyl, ethyl, vinyl, cyclopropyl, or more than one Z joins together to form a 5 or six membered ring;

or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof, in at an amount effective to modulate Ras signaling in at least one cell.

Also disclosed are compounds having a structure represented by a compound of the following formula:



wherein

X1is selected from C1-6—RA;

X2is selected from C1-6—RB;

RAis optionally substituted with one or more Z, and selected from H, alkyl, alkyl-amino, amino, amine, cyano, —OH, alkyl-OH, N—(CH2)1-6—OH, acetamidine, guanidine, N-containing cycloheteroalkyl, N-containing heteroaryl, amino-substituted cycloalkyl, amino-substituted heterocycloalkyl, amino-substituted aryl, halogen, cycloalkyl, heterocycloalkyl, heteroalkenyl, aminocycloalkyl, aminocycloalkenyl;

RBis optionally substituted with one or more Z and selected from H, alkyl, aminoalkyl, cycloalkyl, alkoxy, halogen, cycloheteroalkyl, aryl, heteroaryl,

R1is optionally substituted with one or more Z and selected from alkyl, benzyl, phenyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, alkyl-cycloalkyl, alkyl-aryl, alkyl-heteroaryl, alkenyl-cycloalkyl;

R2is optionally substituted with one or more Z, and selected from phenyl, benzyl, aryl, heteroaryl, alkyl-heteroalkyl, alkyl-heteroaryl, alkyl-cycloalkyl, biaryl, heterobiaryl, alkyl-biaryl, alkenyl, furanyl, thiophenyl, triazolyl, imidazolyl, pyrrolidinyl, thiazolyl, or forms a heteroalkyl ring with itself;

Z is independently H, alkyl, halogen, CF3, alkoxy, alkyl-alkoxy, OH, O—CF3, O-Me, acetonitrile, Cl, F, Br, cyano, CF3, or alkyl, including methyl, ethyl, vinyl, cyclopropyl, or more than one Z joins together to form a 5 or six membered ring;

or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof.

Also disclosed are pharmaceutical compositions comprising a compound having a structure represented by a compound of the following formula:



wherein

X1is selected from C1-6—RA;

X2is selected from C1-6—RB;

RAis optionally substituted with one or more Z, and selected from H, alkyl, alkyl-amino, amino, amine, cyano, —OH, alkyl-OH, N—(CH2)1-6—OH, acetamidine, guanidine, N-containing cycloheteroalkyl, N-containing heteroaryl, amino-substituted cycloalkyl, amino-substituted heterocycloalkyl, amino-substituted aryl, halogen, cycloalkyl, heterocycloalkyl, heteroalkenyl, aminocycloalkyl, aminocycloalkenyl;

RBis optionally substituted with one or more Z and selected from H, alkyl, aminoalkyl, cycloalkyl, alkoxy, halogen, cycloheteroalkyl, aryl, heteroaryl,

R1is optionally substituted with one or more Z and selected from alkyl, benzyl, phenyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, alkyl-cycloalkyl, alkyl-aryl, alkyl-heteroaryl, alkenyl-cycloalkyl;

R2is optionally substituted with one or more Z, and selected from phenyl, benzyl, aryl, heteroaryl, alkyl-heteroalkyl, alkyl-heteroaryl, alkyl-cycloalkyl, biaryl, heterobiaryl, alkyl-biaryl, alkenyl, furanyl, thiophenyl, triazolyl, imidazolyl, pyrrolidinyl, thiazolyl, or forms a heteroalkyl ring with itself;

Z is independently H, alkyl, halogen, CF3, alkoxy, alkyl-alkoxy, OH, O—CF3, O-Me, acetonitrile, Cl, F, Br, cyano, CF3, or alkyl, including methyl, ethyl, vinyl, cyclopropyl, or more than one Z joins together to form a 5 or six membered ring; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof; and a pharmaceutically acceptable carrier.

Also disclosed are methods for modulating Ras signaling in at least one cell comprising the step of contacting at least one cell with at least one disclosed compound in an amount effective to modulate Ras signaling in at least one cell.

Also disclosed herein are methods for modulating Ras signaling in a subject comprising the step of administering to the subject a therapeutically effective amount of at least one disclosed compound in a dosage and amount effective to modulate Ras signaling in the subject.

Also disclosed are methods for the treatment of diseases associated with dysfunctional Ras signaling or cancer associated with dysfunctional Ras signaling comprising the step of administering to the mammal at least one disclosed compound in a dosage and amount effective to treat the disorder in the mammal.

Also disclosed are methods for making a compound comprising the steps of providing a quinazoline compound having a structure represented by a compound of the following formula:


As shown in the Examples below, wherein the variables are defined herein.

Also disclosed are the products of the disclosed methods of making compounds of the present invention.

Also disclosed are methods for the manufacture of a medicament for modulating Ras signaling in a mammal comprising combining a compound of the following formula:



wherein

X1is selected from C1-6—RA;

X2is selected from C1-6—RB;

RAis optionally substituted with one or more Z, and selected from H, alkyl, alkyl-amino, amino, amine, cyano, —OH, alkyl-OH, N—(CH2)1-6—OH, acetamidine, guanidine, N-containing cycloheteroalkyl, N-containing heteroaryl, amino-substituted cycloalkyl, amino-substituted heterocycloalkyl, amino-substituted aryl, halogen, cycloalkyl, heterocycloalkyl, heteroalkenyl, aminocycloalkyl, aminocycloalkenyl;

RBis optionally substituted with one or more Z and selected from H, alkyl, aminoalkyl, cycloalkyl, alkoxy, halogen, cycloheteroalkyl, aryl, heteroaryl,

R1is optionally substituted with one or more Z and selected from alkyl, benzyl, phenyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, alkyl-cycloalkyl, alkyl-aryl, alkyl-heteroaryl, alkenyl-cycloalkyl;

R2is optionally substituted with one or more Z, and selected from phenyl, benzyl, aryl, heteroaryl, alkyl-heteroalkyl, alkyl-heteroaryl, alkyl-cycloalkyl, biaryl, heterobiaryl, alkyl-biaryl, alkenyl, furanyl, thiophenyl, triazolyl, imidazolyl, pyrrolidinyl, thiazolyl, or forms a heteroalkyl ring with itself;

Z is independently H, alkyl, halogen, CF3, alkoxy, alkyl-alkoxy, OH, O—CF3, O-Me, acetonitrile, Cl, F, Br, cyano, CF3, or alkyl, including methyl, ethyl, vinyl, cyclopropyl, or more than one Z joins together to form a 5 or six membered ring; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof with a pharmaceutically acceptable carrier.

Also disclosed are the products of the disclosed methods for the manufacture of medicament.

Also disclosed are uses of a compound for modulating Ras signaling in a mammal, wherein the compound has a structure represented by the following formula:



wherein

X1is selected from C1-6—RA;

X2is selected from C1-6—RB;

RAis optionally substituted with one or more Z, and selected from H, alkyl, alkyl-amino, amino, amine, cyano, —OH, alkyl-OH, N—(CH2)1-6—OH, acetamidine, guanidine, N-containing cycloheteroalkyl, N-containing heteroaryl, amino-substituted cycloalkyl, amino-substituted heterocycloalkyl, amino-substituted aryl, halogen, cycloalkyl, heterocycloalkyl, heteroalkenyl, aminocycloalkyl, aminocycloalkenyl;

RBis optionally substituted with one or more Z and selected from H, alkyl, aminoalkyl, cycloalkyl, alkoxy, halogen, cycloheteroalkyl, aryl, heteroaryl,

R1is optionally substituted with one or more Z and selected from alkyl, benzyl, phenyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, alkyl-cycloalkyl, alkyl-aryl, alkyl-heteroaryl, alkenyl-cycloalkyl;

R2is optionally substituted with one or more Z, and selected from phenyl, benzyl, aryl, heteroaryl, alkyl-heteroalkyl, alkyl-heteroaryl, alkyl-cycloalkyl, biaryl, heterobiaryl, alkyl-biaryl, alkenyl, furanyl, thiophenyl, triazolyl, imidazolyl, pyrrolidinyl, thiazolyl, or forms a heteroalkyl ring with itself;

Z is independently H, alkyl, halogen, CF3, alkoxy, alkyl-alkoxy, OH, O—CF3, O-Me, acetonitrile, Cl, F, Br, cyano, CF3, or alkyl, including methyl, ethyl, vinyl, cyclopropyl, or more than one Z joins together to form a 5 or six membered ring; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof.

Also disclosed are methods for the treatment of diseases associated with dysfunctional Ras signaling in a mammal comprising the step of co-administering to the mammal at least one compound in a dosage and amount effective to treat the dysfunction in the mammal, the composition having a structure represented by the following formula:



wherein

X1is selected from C1-6—RA;

X2is selected from C1-6—RB;

RAis optionally substituted with one or more Z, and selected from H, alkyl, alkyl-amino, amino, amine, cyano, —OH, alkyl-OH, N—(CH2)1-6—OH, acetamidine, guanidine, N-containing cycloheteroalkyl, N-containing heteroaryl, amino-substituted cycloalkyl, amino-substituted heterocycloalkyl, amino-substituted aryl, halogen, cycloalkyl, heterocycloalkyl, heteroalkenyl, aminocycloalkyl, aminocycloalkenyl;

RBis optionally substituted with one or more Z and selected from H, alkyl, aminoalkyl, cycloalkyl, alkoxy, halogen, cycloheteroalkyl, aryl, heteroaryl,

R1is optionally substituted with one or more Z and selected from alkyl, benzyl, phenyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, alkyl-cycloalkyl, alkyl-aryl, alkyl-heteroaryl, alkenyl-cycloalkyl;

R2is optionally substituted with one or more Z, and selected from phenyl, benzyl, aryl, heteroaryl, alkyl-heteroalkyl, alkyl-heteroaryl, alkyl-cycloalkyl, biaryl, heterobiaryl, alkyl-biaryl, alkenyl, furanyl, thiophenyl, triazolyl, imidazolyl, pyrrolidinyl, thiazolyl, or forms a heteroalkyl ring with itself;

Z is independently H, alkyl, halogen, CF3, alkoxy, alkyl-alkoxy, OH, O—CF3, O-Me, acetonitrile, Cl, F, Br, cyano, CF3, or alkyl, including methyl, ethyl, vinyl, cyclopropyl, or more than one Z joins together to form a 5 or six membered ring;

or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof; with a drug having a known side-effect of increasing SOS activity.

Also disclosed are methods for the treatment of diseases associated with dysfunctional Ras signaling in a mammal comprising the step of co-administering to the mammal at least one compound in a dosage and amount effective to treat the dysfunction in the mammal, the composition having a structure represented by the following formula:



wherein

X1is selected from C1-6—RA;

X2is selected from C1-6—RB;

RAis optionally substituted with one or more Z, and selected from H, alkyl, alkyl-amino, amino, amine, cyano, —OH, alkyl-OH, N—(CH2)1-6—OH, acetamidine, guanidine, N-containing cycloheteroalkyl, N-containing heteroaryl, amino-substituted cycloalkyl, amino-substituted heterocycloalkyl, amino-substituted aryl, halogen, cycloalkyl, heterocycloalkyl, heteroalkenyl, aminocycloalkyl, aminocycloalkenyl;

RBis optionally substituted with one or more Z and selected from H, alkyl, aminoalkyl, cycloalkyl, alkoxy, halogen, cycloheteroalkyl, aryl, heteroaryl,

R1is optionally substituted with one or more Z and selected from alkyl, benzyl, phenyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, alkyl-cycloalkyl, alkyl-aryl, alkyl-heteroaryl, alkenyl-cycloalkyl;

R2is optionally substituted with one or more Z, and selected from phenyl, benzyl, aryl, heteroaryl, alkyl-heteroalkyl, alkyl-heteroaryl, alkyl-cycloalkyl, biaryl, heterobiaryl, alkyl-biaryl, alkenyl, furanyl, thiophenyl, triazolyl, imidazolyl, pyrrolidinyl, thiazolyl, or forms a heteroalkyl ring with itself;

Z is independently H, alkyl, halogen, CF3, alkoxy, alkyl-alkoxy, OH, O—CF3, O-Me, acetonitrile, Cl, F, Br, cyano, CF3, or alkyl, including methyl, ethyl, vinyl, cyclopropyl, or more than one Z joins together to form a 5 or six membered ring;

or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof; with a drug having a known side-effect of modulating Ras signaling.

Also disclosed are methods for the treatment of diseases associated with dysfunctional Ras signaling in a mammal comprising the step of co-administering to the mammal at least one compound in a dosage and amount effective to treat the dysfunction in the mammal, the composition having a structure represented by the following formula:



wherein

X1is selected from C1-6—RA;

X2is selected from C1-6—RB;

RAis optionally substituted with one or more Z, and selected from H, alkyl, alkyl-amino, amino, amine, cyano, —OH, alkyl-OH, N—(CH2)1-6—OH, acetamidine, guanidine, N-containing cycloheteroalkyl, N-containing heteroaryl, amino-substituted cycloalkyl, amino-substituted heterocycloalkyl, amino-substituted aryl, halogen, cycloalkyl, heterocycloalkyl, heteroalkenyl, aminocycloalkyl, aminocycloalkenyl;

RBis optionally substituted with one or more Z and selected from H, alkyl, aminoalkyl, cycloalkyl, alkoxy, halogen, cycloheteroalkyl, aryl, heteroaryl,

R1is optionally substituted with one or more Z and selected from alkyl, benzyl, phenyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, alkyl-cycloalkyl, alkyl-aryl, alkyl-heteroaryl, alkenyl-cycloalkyl;

R2is optionally substituted with one or more Z, and selected from phenyl, benzyl, aryl, heteroaryl, alkyl-heteroalkyl, alkyl-heteroaryl, alkyl-cycloalkyl, biaryl, heterobiaryl, alkyl-biaryl, alkenyl, furanyl, thiophenyl, triazolyl, imidazolyl, pyrrolidinyl, thiazolyl, or forms a heteroalkyl ring with itself;

Z is independently H, alkyl, halogen, CF3, alkoxy, alkyl-alkoxy, OH, O—CF3, O-Me, acetonitrile, Cl, F, Br, cyano, CF3, or alkyl, including methyl, ethyl, vinyl, cyclopropyl, or more than one Z joins together to form a 5 or six membered ring;

or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof; with a drug having a known side-effect of having anti-cancer activity.

Also disclosed are methods for the treatment of diseases associated with dysfunctional Ras signaling in a mammal comprising the step of co-administering to the mammal at least one compound in a dosage and amount effective to treat the dysfunction in the mammal, the composition having a structure represented by the following formula:



wherein

X1is selected from C1-6—RA;

X2is selected from C1-6—RB;

RAis optionally substituted with one or more Z, and selected from H, alkyl, alkyl-amino, amino, amine, cyano, —OH, alkyl-OH, N—(CH2)1-6—OH, acetamidine, guanidine, N-containing cycloheteroalkyl, N-containing heteroaryl, amino-substituted cycloalkyl, amino-substituted heterocycloalkyl, amino-substituted aryl, halogen, cycloalkyl, heterocycloalkyl, heteroalkenyl, aminocycloalkyl, aminocycloalkenyl;

RBis optionally substituted with one or more Z and selected from H, alkyl, aminoalkyl, cycloalkyl, alkoxy, halogen, cycloheteroalkyl, aryl, heteroaryl,

R1is optionally substituted with one or more Z and selected from alkyl, benzyl, phenyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, alkyl-cycloalkyl, alkyl-aryl, alkyl-heteroaryl, alkenyl-cycloalkyl;

R2is optionally substituted with one or more Z, and selected from phenyl, benzyl, aryl, heteroaryl, alkyl-heteroalkyl, alkyl-heteroaryl, alkyl-cycloalkyl, biaryl, heterobiaryl, alkyl-biaryl, alkenyl, furanyl, thiophenyl, triazolyl, imidazolyl, pyrrolidinyl, thiazolyl, or forms a heteroalkyl ring with itself;

Z is independently H, alkyl, halogen, CF3, alkoxy, alkyl-alkoxy, OH, O—CF3, O-Me, acetonitrile, Cl, F, Br, cyano, CF3, or alkyl, including methyl, ethyl, vinyl, cyclopropyl, or more than one Z joins together to form a 5 or six membered ring;

or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof; with a drug known to treat cancer.

