Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
  • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
  • A61K47/545—Heterocyclic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
  • C07C233/35—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
  • C07C233/36—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
  • C07C233/35—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
  • C07C233/38—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a carbon atom of an acyclic unsaturated carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
  • C07C233/42—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
  • C07C233/43—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/90—Carboxylic acid amides having nitrogen atoms of carboxamide groups further acylated
  • C07C233/91—Carboxylic acid amides having nitrogen atoms of carboxamide groups further acylated with carbon atoms of the carboxamide groups bound to acyclic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
  • C07C309/78—Halides of sulfonic acids
  • C07C309/79—Halides of sulfonic acids having halosulfonyl groups bound to acyclic carbon atoms
  • C07C309/83—Halides of sulfonic acids having halosulfonyl groups bound to acyclic carbon atoms of a carbon skeleton substituted by nitrogen atoms, not being part of nitro or nitroso groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
  • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
  • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2603/00—Systems containing at least three condensed rings
  • C07C2603/02—Ortho- or ortho- and peri-condensed systems
  • C07C2603/40—Ortho- or ortho- and peri-condensed systems containing four condensed rings
  • C07C2603/42—Ortho- or ortho- and peri-condensed systems containing four condensed rings containing only six-membered rings
  • C07C2603/50—Pyrenes; Hydrogenated pyrenes

Definitions

• the present document features a method of targeting or engaging one or more targets with a chemical compound, the method including: providing the chemical compound to the one or more targets, and incubating the chemical compound with the one or more targets under conditions configured to bind the specificity group to the specific target site and to react the at least two reactive moieties with the respective reactive site to form one or more covalent bonds.
• the chemical compound includes: a specificity group configured to interact with a specific target site of the one or more targets, and at least two reactive moieties.
• each of the at least two reactive moieties is configured to react with a respective reactive site of the one or more targets.
• the present document features a method of identifying one or more targets, the method including: providing a chemical compound to a test sample; and identifying a biological target bound to the chemical compound.
• the chemical compound includes a structure having Formula (I) (e.g., as described herein).
• the present document features a method of treating a disease, the method including: administering a therapeutically effective amount of a chemical compound to a subject in need thereof.
• the chemical compound includes a structure having Formula (I) (e.g., as described herein).
• each of R 7 is, independently, H, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aromatic, optionally substituted aralkyl, optionally substituted alkaryl, optionally substituted heteroaromatic, optionally substituted aryloxy, optionally substituted aralkoxy, optionally substituted aralkanoyl, optionally substituted aralkanoyloxy, optionally substituted aryloyloxy, optionally substituted aryloxycarbonyl, optionally substituted aryloyl, optionally substituted heterocyclyl, halo, hydroxyl, amino, nitro, or cyano.
• the chemical compound and/or the test compound is selected from SH002, SH003, SH004, SH005, SH006, SH009, SH012, SH013, SH014, SH015, SH016, SH017, SH018, SH019, SH020, SH021, SH022, SH023, SH028, SH031, SH032, SH034, SH036, SH037, SH038, SH039, SH040, SH043, or a pharmaceutically acceptable salt thereof.
• the chemical compound and/or the test compound is selected from SH002, SH003, SH004, SH005, SH013, SH014, SH015, SH017, SH018, SH019, SH020, SH021, SH022, SH023, SH028, SH031, SH032, SH034, SH036, SH037, or a pharmaceutically acceptable salt thereof.
• the chemical compound and/or the test compound is selected from SH013, SH031, SH038, SH039, SH043, or a pharmaceutically acceptable salt thereof. Additional details are provided herein. Definitions [0051] As used herein, the term “about” means +/-10% of any recited value.
• alkanoyl or “acyl,” as used interchangeably herein, is meant –C(O)-R, in which R is hydrogen, an optionally substituted aliphatic group, or an optionally substituted alkyl group, as defined herein.
• the aliphatic or alkyl groups can be substituted or unsubstituted.
• the aliphatic or alkyl groups can be substituted with one or more substitution groups, as described herein for alkyl.
• alkanoyloxy is meant –O-C(O)-R, in which R is hydrogen, an optionally substituted aliphatic group, or an optionally substituted alkyl group, as defined herein.
• the aliphatic or alkyl groups can be substituted or unsubstituted.
• the aliphatic or alkyl groups can be substituted with one or more substitution groups, as described herein for alkyl.
• alkaryl is meant –Ar-Ak, where Ar is an optionally substituted arylene group and Ak is an optionally substituted aliphatic group or optionally substituted alkyl group, as described herein.
• the arylene, aliphatic, and alkyl groups can be substituted or unsubstituted.
• the arylene, aliphatic, and alkyl groups can be substituted with one or more substitution groups, as described herein for alkyl or aryl.
• alkenyl group can also be substituted or unsubstituted.
• the alkenyl group can be substituted with one or more substitution groups, as described herein for alkyl.
• alkenyloxy is meant —OR, where R is an optionally substituted alkenyl group, as described herein.
• alkenylsulfonyl is meant —SO 2 R, where R is an optionally substituted alkenyl group, as described herein.
• alkoxy is meant –OR, where R is an optionally substituted aliphatic group or an optionally substituted alkyl group, as described herein.
• alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec- butoxy, n-pentoxy, haloalkoxy (e.g., trihaloalkoxy, such as trifluoromethoxy, dihaloalkoxy, such as difluoromethoxy, monohaloalkoxy, and the like), etc.
• the alkoxy group can be substituted or unsubstituted.
• the alkoxy group can be substituted with one or more substitution groups, as described herein for alkyl.
• alkoxycarbonyl is meant –C(O)-OR, where R is an optionally substituted aliphatic group or an optionally substituted alkyl group, as described herein.
• R is an optionally substituted aliphatic group or an optionally substituted alkyl group, as described herein.
• the alkoxycarbonyl group can be substituted or unsubstituted.
• the alkoxycarbonyl group can be substituted with one or more substitution groups, as described herein for alkyl.
• the alkyl group can be cyclic (e.g., C3-24 cycloalkyl) or acyclic.
• the alkyl group can be branched or unbranched.
• the alkyl group can also be substituted or unsubstituted.
• alkyleneoxy groups include methyleneoxy, ethyleneoxy, propyleneoxy, butyleneoxy, etc.
• the alkyleneoxy group is a C1-3, C1-6, C1-12, C1-16, C1-18, C1-20, C1-24, C2-3, C2-6, C2-12, C2-16, C2-18, C2-20, or C2-24 alkyleneoxy group.
• the alkyleneoxy group can be branched or unbranched.
• the alkyleneoxy group can also be substituted or unsubstituted.
• the alkyleneoxy group can be substituted with one or more substitution groups, as described herein for alkyl.
• aralkyl is meant —Ak-Ar, where Ak is an optionally substituted alkylene group and Ar is an optionally substituted aromatic group or optionally substituted aryl group, as described herein.
• the alkylene, aromatic, and aryl groups can be substituted or unsubstituted.
• the alkylene, aromatic, and aryl groups can be substituted with one or more substitution groups, as described herein for alkyl or aryl.
• Exemplary unsubstituted aralkyl groups include C4-18 aryl-C1-3 alkyl, C4-18 aryl-C1-6 alkyl, and C4-18 aryl- C1-12 alkyl groups.
• aralkoxy is meant —O-Ak-Ar, where Ak is an optionally substituted alkylene group and Ar is an optionally substituted aromatic group or optionally substituted aryl group, as described herein.
• the alkylene, aromatic, and aryl groups can be substituted or unsubstituted.
• the alkylene, aromatic, and aryl groups can be substituted with one or more substitution groups, as described herein for alkyl or aryl.
• Exemplary unsubstituted aralkoxy groups include C 4-18 aryl-C 1-3 alkoxy, C 4-18 aryl-C 1-6 alkoxy, and C 4-18 aryl-C1-12 alkoxy groups.
• aromatic also includes “heteroaromatic,” as described herein.
• aryl is meant a group that contains any carbon-based aromatic group including, but not limited to, benzyl, naphthalene, phenyl, biphenyl, phenoxybenzene, and the like.
• aryl also includes “heteroaryl,” which is defined as a group that contains an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus.
• the arylene group is a C4-18, C4-14, C4-12, C 4-10 , C 6-18 , C 6-14 , C 6-12 , or C 6-10 arylene group.
• the arylene group can be branched or unbranched.
• the arylene group can also be substituted or unsubstituted.
• the arylene group can be substituted with one or more substitution groups, as described herein for alkyl or aryl.
• aryloxy is meant –O-Ar, where Ar is an optionally substituted aromatic group or optionally substituted aryl group, as described herein.
• the aromatic or aryl group can be substituted or unsubstituted.
• arylsulfonyl is meant —SO 2 R, where R is an optionally substituted aromatic group or an optionally substituted aryl group, as described herein.
• the arylsulfonyl group can be substituted or unsubstituted.
• the arylsulfonyl group can be substituted with one or more substitution groups, as described herein for alkyl or aryl.
• click chemistry signature refers to a plurality of atoms disposed between and covalently linking entity A and entity B, in which the click chemistry signature is formed as the product of a click reaction that links entity A and entity B.
• the click chemistry signature has the structure of a click chemistry signature that is formed as the product of a click reaction that links entity A and entity B, but is not limited to a click chemistry signature made by any particular process, e.g., not limited to a click chemistry signature formed by a click reaction, but can be formed or provided by another process.
• heteroaryl is meant an aryl group including at least one heteroatom to six heteroatoms, such as one to four heteroatoms, which can be selected from, but not limited to, oxygen, nitrogen, sulfur, silicon, boron, selenium, phosphorous, and oxidized forms thereof within the ring.
• Such heteroaryl groups can have a single ring or multiple condensed rings, where the condensed rings may or may not be aromatic and/or contain a heteroatom, provided that the point of attachment is through an atom of the aromatic heteroaryl group.
• Heteroaryl groups may be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, aromatic, other functional groups, or any combination thereof.
• heteroatom is meant an atom other than carbon, such as oxygen, nitrogen, sulfur, silicon, boron, selenium, or phosphorous. In particular disclosed embodiments, such as when valency constraints do not permit, a heteroatom does not include a halogen atom.
• heterocyclyl or “heterocyclic” is meant a 5-, 6-, or 7-membered ring, unless otherwise specified, containing one, two, three, or four non-carbon heteroatoms (e.g., independently selected from the group consisting of nitrogen, oxygen, phosphorous, sulfur, or halo).
• heterocyclyl also includes bicyclic, tricyclic and tetracyclic groups in which any of the above heterocyclic rings is fused to one, two, or three rings independently selected from the group consisting of an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, and another monocyclic heterocyclic ring, such as indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl, benzothienyl and the like.
• Exemplary unsubstituted thioalkoxy groups include C 1-3 , C 1-6 , C 1-12 , C 1-16 , C 1-18 , C 1-20 , or C 1-24 thioalkoxy groups.
• thioaryloxy is meant –S-Ar, where Ar is an optionally substituted aromatic group or optionally substituted aryl group, as described herein.
• the thioaryloxy group can be substituted or unsubstituted.
• the thioaryloxy group can be substituted with one or more substitution groups, as described herein for alkyl or aryl.
• cationic salts include organic salts, such as chloroprocaine, choline, dibenzylethylenediamine, diethanolamine, ethylenediamine, methylglucamine, and procaine.
• pharmaceutically acceptable salt is meant a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.
• pharmaceutically acceptable excipient is meant any ingredient other than a compound or structure (e.g., any formulas, compounds, or compositions described herein) and having the properties of being non-toxic and non-inflammatory in a subject.
• Administration can be carried out by any suitable route.
• a suitable route of administration allows the compound or the composition to perform its intended function.
• the terms “subject,” “individual,” and “patient” are used interchangeably herein and refer to any animal subject for whom diagnosis, treatment, or therapy is desired, particularly humans.
• the subject is a mammal (e.g., a human subject).
• the subject is a non-human mammal (e.g., mouse, rat, guinea pig, dog, cat, horse, cow, pig, rabbit, sheep, or non-human primate, such as a monkey, chimpanzee, or baboon).
• an effective amount can be administered to a subject susceptible to, or otherwise at risk of developing a disease, disorder or condition to eliminate or reduce the risk, lessen the severity, or delay the onset of the disease, disorder or condition, including a biochemical, histologic and/or behavioral symptoms of the disease, disorder or condition, its complications, and intermediate pathological phenotypes.
• the terms “treat,” “treating,” and/or “treatment” include abrogating, substantially inhibiting, slowing or reversing the progression of a disorder, disease or condition, substantially ameliorating clinical symptoms of a disorder, disease or condition, or substantially preventing the appearance of clinical symptoms of a disorder, disease or condition, obtaining beneficial or desired clinical results.
• Treating further refers to accomplishing one or more of the following: (a) reducing the severity of the disorder, disease or condition); (b) limiting development of symptoms characteristic of the disorder, disease or condition(s) being treated; (c) limiting worsening of symptoms characteristic of the disorder, disease or condition(s) being treated; (d) limiting recurrence of the disorder, disease or condition(s) in subjects that have previously had the disorder, disease or condition(s); and (e) limiting recurrence of symptoms in subjects that were previously asymptomatic for the disorder, disease or condition(s).
• Beneficial or desired clinical results include, but are not limited to, preventing the disease, disorder or condition from occurring in a subject predisposed to the disease, disorder or condition but does not yet experience or exhibit symptoms of the disease (prophylactic treatment), alleviation of symptoms of the disease, disorder or condition, diminishment of extent of the disease, disorder or condition, stabilization (e.g., not worsening) of the disease, disorder or condition, preventing spread of the disease, disorder or condition, delaying or slowing of the disease, disorder or condition progression, amelioration or palliation of the disease, disorder or condition, and combinations thereof, as well as prolonging survival as compared to expected survival if not receiving treatment.
• FIG.1A-1C shows schematics of (A) a non-limiting compound having a specificity group (SG) and a reactive moiety (RM); (B) a non-limiting interaction of a compound with a target having a specific target site and a reactive site; and (C) a non-limiting interaction of a compound with a multimeric target having a specific target site and a reactive site.
• FIG.2A-2B shows schematics of (A) another non-limiting compound having a specificity group (SG, including SG1 and SG2) and a reactive moiety (RM, including RM1 and RM2); and (B) a non-limiting interaction of a compound with two targets that each have a specific target site and a reactive site.
• FIG.3A-3B shows structures of non-limiting compounds, which include IC9 and SH001-SH021. Abbreviations are as follows: benzyl (Bn), methyl (Me), tert-butyl (tBu), and benzoyl (Bz).
• FIG.4A-4D shows structures of non-limiting compounds, which include SH022- SH053. Abbreviations are as follows: phenyl (Ph), benzyl (Bn), and methyl (Me).
• FIG.5 shows non-limiting results of cysteine druggability mapping (CDM) for cell models H3122 and H2228.
• CDM cysteine druggability mapping
• FIG.17A-17B shows (A) non-limiting results of 1C9 dimerizing a protein including an EML4 coiled-coil domain, cysteine, and GFP and (B) non-limiting schematics of dimer, trimer, and tetramer configurations that could be implemented.
• FIG.18 shows a non-limiting schematic of the gene fusion of EML4 and ALK, which results in constitutive activation of ALK signaling and drives cancer.
• FIG.19A-19C shows non-limiting schematics of (A) targetable cysteine groups, (B) a cysteine druggability mapping (CDM) of cell model H3122, and (C) non-limiting examples of inhibitor drugs and targets.
• CDM cysteine druggability mapping
• FIG.20A-20C shows non-limiting schematics for performing a small molecule screen with (A) pooled compounds from a library and (B) individual compounds within a pool to provide (C) screening identification of possible compounds.
• FIG.21A-21B shows non-limiting results that (A) EML4 dimerization occurs in the presence of at least one cysteine and (B) 1C9 dimerizes ALK resistant mutant cells.
• FIG.22 shows non-limiting results that EML4-ALK crosslinking leads to degradation.
• FIG.23A-23B shows non-limiting results of live-cell imaging that was conducted at the single-cell level within 24 hours of treatment.
• the specificity group of the chemical compound binds to one or more specific target sites of the multimeric target (e.g., one portion of the multimeric target).
• the reactive moieties of the chemical compound e.g., here RM1 and RM2
• reacts with respective reactive sites of the target thereby forming one or more covalent bonds (e.g., within the multimeric target).
• covalent bonds are formed within a single portion of the multimeric target.
• covalent bonds are formed between differing portions of the multimeric target.
• the chemical compound can include a reactive moiety that can react with a cysteine (e.g., a thiol group of the cysteine).
• the reactive moiety can include a leaving group that favorably reacts with cysteine to form a covalent bond.
• Such a compound can form a class of covalent cysteine-reactive inhibitors.
• One non-limiting target for such inhibitors can include the EML4-ALK protein, which provides a constitutively active ALK kinase domain.
• the chemical compound can be used to inhibit the kinase activity of EML4-ALK oncogene.
• the compound includes a structure of Formula (I): wherein: S includes a scaffold (e.g., a linking moiety, including a multivalent linker); each SG includes, independently, a specificity group configured to interact with a respective specific target site of the one or more targets; each of RM1 and RM2 includes, independently, a reactive moiety configured to react with a respective reactive site of the one or more targets to form covalent bonds; and n is an integer of 1 or more (e.g., 1, 2, or more).
• S includes a scaffold (e.g., a linking moiety, including a multivalent linker)
• each SG includes, independently, a specificity group configured to interact with a respective specific target site of the one or more targets
• each of RM1 and RM2 includes, independently, a reactive moiety configured to react with a respective reactive site of the one or more targets to form covalent bonds
• n is an integer of 1 or more (e.g., 1, 2, or more).
• the compound includes a structure of Formula (Ia): pharmaceutically acceptable salt thereof; wherein: S includes a scaffold (e.g., a linking moiety, including a multivalent linker); each of SG and SG’ includes, independently, a specificity group configured to interact with a respective specific target site of the one or more targets; each L includes, independently, a linker (e.g., a covalent bond, oxy, carbonyl, imino, nitrilo, an atom, an optionally substituted alkylene group, an optionally substituted alkyleneoxy group, an optionally substituted heteroalkylene group, an optionally substituted arylene group, or an optionally substituted heteroarylene group, which can further optionally include a click chemistry signature, as well as any described herein); each of RM1 and RM2 includes, independently, a reactive moiety configured to react with a respective reactive site of the one or more targets to form covalent bonds; each M includes, independently, a
• the compound e.g., at least one of a plurality of test compounds in a library
• the compound includes a structure having Formula (II): pharmaceutically acceptable salt thereof; wherein: S includes a scaffold (e.g., a trivalent or tetravalent linker); each SG includes, independently, a specificity group configured to interact with a respective specific target site of one or more targets (e.g., includes one or more aromatic groups; or one or more other targeting compounds); each of R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is, independently, H, halo, optionally substituted C112 aliphatic, or optionally substituted C1-12 heteroaliphatic; each of X 1 and X 2 is, independently, halo, a leaving group, or an electrophilic group, or wherein X 1 and R 3 , when taken together with the carbon atom to which each are attached, forms an optionally
• At least one of w1 and w2 is an integer greater than 0. In some embodiments, w1 and w2 are both 0, or at least one of w1 and w2 is 0. In some embodiments, x is an integer greater than 0. In some embodiments, at least one of y, ya, and yb is an integer greater than 0. In some embodiments, z is an integer greater than 0.
• the compound includes a structure having Formula (III): pharmaceutically acceptable salt thereof; wherein: L1 includes a linker (e.g., a covalent bond, a bivalent linker, a trivalent linker, oxy, carbonyl, carbonyloxy, imino, nitrilo, sulfo, an atom, an optionally substituted aliphatic group, an optionally substituted alkylene group, an optionally substituted alkyleneoxy group, an optionally substituted heteroaliphatic group, an optionally substituted heteroalkylene group, an optionally substituted aromatic group, an optionally substituted arylene group, an optionally substituted heteroarylene group, or an optionally substituted heterocyclic group, which can further optionally include a click chemistry signature, as well as any described herein); each of R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is, independently, H, halo, optionally substituted C 1- 12 alipha
• the compound includes a structure having Formula (IV) or (V): y acceptable salt thereof; wherein: L1 includes a linker (e.g., a covalent bond, a bivalent linker, a trivalent linker, oxy, carbonyl, carbonyloxy, imino, nitrilo, sulfo, an atom, an optionally substituted aliphatic group, an optionally substituted alkylene group, an optionally substituted alkyleneoxy group, an optionally substituted heteroaliphatic group, an optionally substituted heteroalkylene group, an optionally substituted aromatic group, an optionally substituted arylene group, an optionally substituted heteroarylene group, or an optionally substituted heterocyclic group, which can further optionally include a click chemistry signature, as well as any described herein); each of R 1a , R 1b , R 2 , R 2a , R 2b , R 2c , R 2d , R 3 , R
• the compound e.g., any herein, such as a compound of having any one of Formulas (I), (Ia), (II), (IIa), (III), (IV), (V), and (1)-(25)
• a linker e.g., any described herein disposed between at least one of the S, SG, R 1 , R 2 , R 3 , R 4 , R 5 , or R 6 and the E3 ligand.
• the specificity group, SG, and/or SG’ if present, includes an aromatic group (e.g., which can also include a heteroaromatic group).
• the aromatic group includes an optionally substituted aryl, phenyl, benzyl, biphenyl, naphthyl, pyrenyl, indenyl, fluorenyl, phenalenyl, phenanthryl, anthryl, triphenylenyl, tetracenyl, acenaphthenyl, carbazolyl (dibenzopyrrolyl), dibenzofuranyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, thiazolyl, or the like.
• the linker (e.g., linker L that may optionally be attached to M) includes –L A -L B -L C –, wherein: each of L A , L B , and L C includes, independently, a linker (e.g., a covalent bond, oxy, carbonyl, carbonyloxy, sulfo, an atom, an optionally substituted alkylene group, an optionally substituted alkyleneoxy group, an optionally substituted heteroalkylene group, an optionally substituted arylene group, or an optionally substituted heteroarylene group, which can further optionally include a click chemistry signature, as well as any described herein).
• a linker e.g., a covalent bond, oxy, carbonyl, carbonyloxy, sulfo, an atom, an optionally substituted alkylene group, an optionally substituted alkyleneoxy group, an optionally substituted heteroalkylene group, an optionally substituted arylene group, or an optional
• each of L A and L B is, independently, a covalent bond, oxy, carbonyl, carbonyloxy, imino, nitrilo, sulfo, an atom, an optionally substituted alkylene group, an optionally substituted alkyleneoxy group, an optionally substituted heteroalkylene group, an optionally substituted arylene group, or an optionally substituted heteroarylene group.
• L C includes a click chemistry signature (e.g., an optionally substituted triazolyl).
• one or more aromatic groups is substituted with one or more groups selected from optionally substituted aliphatic (e.g., alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl), optionally substituted heteroaliphatic (e.g., alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, alkanoyl, alkanoyloxy), optionally substituted aromatic, optionally substituted aralkyl, optionally substituted alkaryl, optionally substituted heteroaromatic, optionally substituted aryloxy, optionally substituted aralkoxy, optionally substituted aralkanoyl, optionally substituted aralkanoyloxy, optionally substituted aryloyloxy, optionally substituted aryloxycarbonyl, optionally substituted aryloyl
• R 7 is H, halo, hydroxyl, nitro, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkoxy, optionally substituted alkenyloxy, or optionally substituted alkynyloxy.
• at least one of R 7 and R 8 is not H.
• each of R 7 , R 8 , R 8a , and R 8b is, independently, H, halo, hydroxyl, nitro, cyano, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted hydroxyalkyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted alkanoyl, optionally substituted alkanoyloxy, optionally substituted aromatic, optionally substituted aryl, optionally substituted aralkyl, optionally substituted alkaryl, optionally substituted aryloxy, optionally substituted aralkoxy, optionally substituted aralkanoyl, optionally substituted aralkanoyloxy, optionally substituted aryloyloxy, optionally substituted aryloxycarbonyl, optionally substituted
• R 8 is not H. In some embodiments, R 8 is not halo. In some embodiments, R 8 is not alkyl. [0190] In any embodiment herein, R 8 , R 8a , and R 8b are not H. In some embodiments, R 8 , R 8a , and R 8b are not halo. In some embodiments, R 8 , R 8a , and R 8b are not alkyl.
• R 8 , R 8a (if present), and R 8b (if present) is, independently, H, halo, hydroxyl, nitro, cyano, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted hydroxyalkyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted alkanoyl, optionally substituted alkanoyloxy, optionally substituted aromatic, optionally substituted aryl, optionally substituted aralkyl, optionally substituted alkaryl, optionally substituted aryloxy, optionally substituted aralkoxy, optionally substituted aralkanoyl, optionally substituted aralkanoyloxy, optionally substituted aryloyloxy, optionally substituted aryloxycarbonyl, optionally substituted
• R 8 , R 8a (if present), and R 8b (if present) is, independently, H, halo, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted alkanoyl, optionally substituted alkanoyloxy, optionally substituted aromatic, optionally substituted aryl, optionally substituted aralkyl, optionally substituted alkaryl, optionally substituted aryloxy, optionally substituted aralkoxy, optionally substituted aralkanoyl, optionally substituted aralkanoyloxy, optionally substituted aryloyloxy, optionally substituted aryloxycarbonyl, optionally substituted aryloyl, optionally substituted heteroaromatic, optionally substituted hetero
• R 8 , R 8a (if present), and R 8b (if present) is, independently, halo, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted alkanoyl, optionally substituted alkanoyloxy, optionally substituted aromatic, optionally substituted aryl, optionally substituted aralkyl, optionally substituted alkaryl, optionally substituted aryloxy, optionally substituted aralkoxy, optionally substituted aralkanoyl, optionally substituted aralkanoyloxy, optionally substituted aryloyloxy, optionally substituted aryloxycarbonyl, optionally substituted aryloyl, optionally substituted heteroaromatic, optionally substituted heterocyclyl, or optionally substituted heteroaryl.
• the compound e.g., within the scaffold or S
• linkers can include any described herein.
• oxy e.g., ⁇ O ⁇
• carbonyl e.g., ⁇ C(O) ⁇
• the composition is a pharmaceutical composition.
• the pharmaceutical composition includes a chemical compound (e.g., any described herein) and a pharmaceutically acceptable excipient.
• the chemical compound is present in a therapeutically effective amount for a unit dosage form.
• unit dosage forms include an oral dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup), a topical dosage form (e.g., a cream, gel, lotion, or ointment), or an intravenous dosage form (e.g., as a sterile solution).
• any of the compounds herein can be provided in a library.
• the library can be encoded to provide the identity of the compound.
• the library can include a plurality of compounds (e.g., including one or more of any compounds herein) provided in any useful format (e.g., beads, wells, arrays, etc.).
• Methods [0197] The present document encompasses methods of using a compound (e.g., any described herein).
• a non-limiting method can include a method of targeting or engaging one or more targets with a chemical compound (e.g., any described herein).
• the method includes: binding a specificity group (e.g., SG, such as any described herein) of the chemical compound to a specific target site, and reacting at least two reactive moieties (e.g., RM, such as RM1, RM2, or any described herein) of the chemical compound with respective reactive sites to form covalent bonds.
• a specificity group e.g., SG, such as any described herein
• RM reactive moieties
• the one or more targets includes the specific target site and at least two reactive sites.
• the one or more targets can include a monomeric protein, a multimeric protein, a single protein, or a plurality of proteins.
• the chemical compound includes a scaffold (e.g., S, such as any described herein) disposed between the specificity group and the at least two reactive moieties.
• a non-limiting method can include a method of targeting or engaging one or more targets with a chemical compound, the method including: providing a chemical compound (e.g., any described herein) to the one or more targets, and incubating the chemical compound with the one or more targets under conditions configured to bind the specificity group to the specific target site and to react the at least two reactive moieties with the respective reactive site to form covalent bonds.
• the chemical compound includes: a specificity group (e.g., SG, such as any described herein) configured to interact with a specific target site of the one or more targets, and at least two (e.g., two, three, four, or more) reactive moieties (e.g., RM, such as RM1, RM2, or any described herein), wherein each of the at least two reactive moieties is configured to react with a respective reactive site of the one or more targets.
• a specificity group e.g., SG, such as any described herein
• RM reactive moieties
• a non-limiting method can include a method of targeting or engaging one or more targets with a chemical compound, the method including: providing an effective amount of the chemical compound, wherein the chemical compound includes a structure having any one of Formulas (I), (Ia), (II), (IIa), (III), (IV), (V), and (1)-(25), or a pharmaceutically acceptable salt thereof.
• the chemical compound is one or more of SH001-SH053, or a pharmaceutically acceptable salt thereof.
• the chemical compound is one or more of SH002, SH003, SH004, SH005, SH006, SH009, SH012, SH013, SH014, SH015, SH016, SH017, SH018, SH019, SH020, SH021, SH022, SH023, SH028, SH031, SH032, SH034, SH036, SH037, SH038, SH039, SH040, SH043, or a pharmaceutically acceptable salt thereof.
• a non-limiting method can include a method of identifying one or more targets, the method including: providing a chemical compound to a test sample, wherein the chemical compound includes a structure having any one of Formulas (I), (Ia), (II), (IIa), (III), (IV), (V), and (1)-(25), or a pharmaceutically acceptable salt thereof; and identifying a biological target bound to the chemical compound.
• the chemical compound is one or more of SH001-SH053, or a pharmaceutically acceptable salt thereof.
• a non-limiting method can include a method of treating a disease (e.g., cancer), the method including: administering a therapeutically effective amount of a chemical compound to a subject in need thereof, wherein the chemical compound includes a structure having any one of Formulas (I), (Ia), (II), (IIa), (III), (IV), (V), and (1)-(25), or a pharmaceutically acceptable salt thereof.
• the chemical compound is one or more of SH001-SH053, or a pharmaceutically acceptable salt thereof.
• the chemical compound is one or more of SH002, SH003, SH004, SH005, SH006, SH009, SH012, SH013, SH014, SH015, SH016, SH017, SH018, SH019, SH020, SH021, SH022, SH023, SH028, SH031, SH032, SH034, SH036, SH037, SH038, SH039, SH040, SH043, or a pharmaceutically acceptable salt thereof.
• the disease is cancer.
• Non-limiting examples include non- small cell lung cancer (NSCLC), lung adenocarcinoma, lung cancer, breast cancer, and colorectal cancer.
• the cancer is characterized by a presence of an EML4-ALK fusion gene, an EML4-ALK fusion protein, an EML4 fusion gene, an EML4 fusion protein, an ALK fusion gene, an ALK fusion protein, or a variant thereof.
• the non-small cell lung cancer is characterized by a presence of an EML4-ALK fusion gene, an EML4-ALK fusion protein, an EML4 fusion gene, an EML4 fusion protein, an ALK fusion gene, an ALK fusion protein, or a variant thereof.
• the specificity group and/or the scaffold includes an E3 ubiquitin ligase (E3) ligand.
• the compound e.g., any described herein
• the linker e.g., any described herein
• the present document relates to compounds and methods for binding, targeting, or otherwise interacting within any target.
• the target includes a protein, a peptide, a fusion protein, or a constitutively active receptor protein.
• Non-limiting examples of targets include, e.g., EML4-ALK, EML4, EML4 fusion protein, ALK fusion protein, PSME1, PSME2, TMX1, TXN, TJP2, PDIA6, P4HB, AGR2, PDIA3, PDIA4, PPFIA1, SMARCC2, GCLC, NPEPPS, PDCD61P, PRDXl, ERO1A, PCBP1, CTTN, PRDX2, PRDX3, RARS1, TXNDC17, RPL21, S100A2, KIF5B, or RPL18.
• EML4-ALK EML4-ALK
• EML4 fusion protein ALK fusion protein
• the one or more targets includes an ALK fusion protein having one or more optional mutations (e.g., 1151T- ins, L1152R/P, C1156Y, I1171T/N/S, F1174L/C/V, V1180L, L1196M/F, L1198P, G1202R/del, D1203N, S1206Y, E1210K, and/or G1269A, including combinations of any of these, such as L1196M/G1202R).
• Targets can also be characterized by the presence of certain structural domains or interactions.
• the one or more targets includes a coiled-coil domain.
• the specific target site includes the coiled-coil domain.
• Targets can also be characterized by the presence of certain functional groups (e.g., amino acids).
• the one or more targets includes one or more cysteines.
• at least two reactive sites includes at least two cysteines.
• the reactive site includes the cysteine.
• Targets can be present, e.g., within a cell, a culture, a tissue sample, a lysate, a sample, and the like.
• the method, the chemical compound, or the test compound inhibits the one or more targets.
• the method, the chemical compound, or the test compound inhibits signaling of the one or more target (e.g., wherein the signaling includes signaling of kinase activity).
• Ligands Any of the compounds herein can include a ligand. In some embodiments, the ligand can engage, bind, or otherwise interact with an E3 ubiquitin ligase. In turn, such a ligand can be an E3 ligand.
• Non-limiting examples of ligands include, e.g., a thalidomide-based ligand, a pomalidomide-based ligand, a 4-hydroxythalidomide-based ligand, a lenalidomide-based ligand, a VH032-based ligand, a VHL ligand 1 (VHL Al)-based ligand, a nutlin-3-based ligand, an idasanutlin-based ligand, a bestatin-based ligand, a methyl bestatin-based ligand, a LCL-161-based ligand, and the like.
• the ligand can be provided in any useful manner.
• the ligand is a substitution for or attached to one or more of S, SG, SG’, A1, A2, Ar 1 , Ar 2 , R 7 , R 8 , R 8a , and R 8b .
• Linkers can be present between two components (e.g., between a click chemistry entity and a ligand, between a reactive group and ligand, etc.) or within a scaffold or S.
• Linkers can include a bond (e.g., a covalent bond); an optionally substituted alkylene; an optionally substituted heteroalkylene (e.g., poly(ethylene glycol), such as ⁇ (OCH 2 CH 2 ) n ⁇ , in which n is an integer of 1 to 100); an optionally substituted arylene; or an optionally substituted heteroarylene, as well as combinations thereof.
• An alkylene can include a multivalent (e.g., bivalent, trivalent, tetravalent, etc.) form of an alkyl group.
• Exemplary alkylene groups include methylene, ethylene, propylene, butylene, etc.
• the alkylene group is a C1-3, C1-6, C1-12, C1-16, C1-18, C1-20, C 1-24 , C 2-3 , C 2-6 , C 2-12 , C 2-16 , C 2-18 , C 2-20 , or C 2-24 alkylene group.
• the alkylene group can be branched or unbranched.
• the alkylene group can also be substituted or unsubstituted.
• the alkylene group can be substituted with one or more substitution groups (e.g., halo, oxy, oxo, amino, and the like).
• a heteroalkylene can be an alkylene group containing one, two, three, or four non-carbon heteroatoms (e.g., independently selected from the group consisting of nitrogen, oxygen, phosphorous, sulfur, or halo).
• the linker can include one or more chemical signatures.
• the chemical signature includes a click-chemistry signature, which arises from reacting a click- chemistry reaction pair (e.g., any described herein).
• Non-limiting examples of click-chemistry signatures include a triazole, an unsaturated six-member ring, a covalent bond, and the like.
• the chemical signature can include a reaction signature, which arises from reacting a cross-linker reaction pair.
• cross-linkers include those for forming a covalent bond between an amino group (e.g., ⁇ NH 2 ) and a thymine moiety, such as succinimidyl-[4-(psoralen-8-yloxy)]-butyrate (SPB); a hydroxyl group (e.g., ⁇ OH) and a sulfur-containing group (e.g., free thiol, ⁇ SH, sulfhydryl, cysteine moiety, or mercapto group), such as p-maleimidophenyl isocyanate (PMPI); between an amino group (e.g., ⁇ NH2) and a sulfur-containing group (e.g., free thiol, ⁇ SH, sulfhydryl, cysteine moiety, or mercapto group), such as succinimidyl 4-(p- maleimidophenyl)butyrate (SMPB) and/or succinimidyl 4-(N-maleimidomethyl)cycl
• cross-linkers include those for forming a covalent bond between two or more unsaturated hydrocarbon bonds, e.g., mediated by radical polymerization, such as a reaction of forming a covalent bond between a first alkene group and a second alkene group (e.g., a reaction between acrylate-derived monomers to form a polyacrylate, polyacrylamide, etc.).
• the linker can include one or more reaction pairs.
• the reaction pair is one of a click-chemistry reaction pair, which can include a first click-chemistry group and a second click-chemistry group that reacts with that first click-chemistry group.
• Exemplary click-chemistry groups include, e.g., a click-chemistry group, e.g., one of a click- chemistry reaction pair selected from the group consisting of a Huisgen 1,3-dipolar cycloaddition reaction between an alkynyl group and an azido group to form a triazole- containing linker; a Diels-Alder reaction between a diene having a 4 ⁇ electron system (e.g., an optionally substituted 1,3-unsaturated compound, such as optionally substituted 1,3-butadiene, 1-methoxy-3-trimethylsilyloxy-1,3-butadiene, cyclopentadiene, cyclohexadiene, or furan) and a dienophile or heterodienophile having a ⁇ electron system (e.g., an optionally substituted alkenyl group or an optionally substituted alkynyl group); a ring opening reaction with a nucleophile and a
• the linker can include a binding reaction signature, which arises from reacting a binding reaction pair.
• binding groups and binding reaction pairs include those for forming a covalent bond between biotin and avidin, biotin and streptavidin, biotin and neutravidin, desthiobiotin and avidin (or a derivative thereof, such as streptavidin or neutravidin), hapten and an antibody, an antigen and an antibody, a primary antibody and a secondary antibody, and lectin and a glycoprotein.
• Cysteine druggability mapping was used to profile ALK fusion cell lines and patient tissues (FIG.5).
• a small molecule screen was performed with a library (e.g., +2,500) of advanced cysteine reactive inhibitors to identify compounds that bind covalently to targets identified in CDM analysis (FIG.6).
• compound 1C9 was identified, and its mechanism of action in dimerizing EML4 was investigated (FIG.7A-7B).
• the interaction of EML4-ALK domains with 1C9 was studied.
• the coiled-coiled domain of EML4 is present during dimerization (FIG.8A-8B).
• FIG.9A-9C Reactive cysteines in EML4 were tested with 1C9 by alanine mutation of cysteine positions (FIG.10A-10B).
• FIG.11 provides a non-limiting hypothesis of 1C9 action.
• an aromatic group e.g., such as benzyl, phenyl, and the like
• the specific target site can include the coiled-coiled domain.
• compounds can include one or more specificity groups that bind to a specific target site in the engineered domain, as well as one or more reactive moieties that react with and form covalent bonds with reactive sites in proximity to the engineered domain.
• Example 2 Overcoming ALK resistance with covalent inhibitors in lung cancer
• the EML4-ALK fusion gene (see, e.g., FIG.18) is the main oncogenic driver in 5% of non-small cell lung cancer and has been effectively targeted using ALK-specific tyrosine kinase inhibitors (ALK TKI). While survival rates have improved steadily with each new generation of ALK TKI, resistance generally develops, including second site ALK kinase mutations as well as by-pass track activation.
• cysteine druggability mapping (CDM) a proteome-wide mass spectrometry target engagement assay, the landscape of reactive cysteines in ALK-positive cell lines was determined, thereby identifying various targetable cysteines within the MAPK pathway and within the EML4-ALK fusion protein itself.
• CDM cysteine druggability mapping
• a high-content phosphorylated protein screen was conducted by testing 4,400 reactive cysteine compounds in a multiplex library including 10 compounds per pool (FIG.20A) and in an expanded library including individual compounds (FIG.20B). About 20 potential hits were identified that impacted ALK phosphorylation or expression (FIG.20C).
• a compound can be configured to bind covalently to at least one cysteine in EML4-ALK and can facilitate crosslinking (e.g., dimerization, trimerization, etc.) of the EML4-ALK, resulting in its degradation (FIG.27).
• Hit-to-lead development can include identifying a compound that binds to the EML4 portion of the fusion, and its mechanism of action can be assessed.
• a library of compounds e.g., several hundred analog compounds
• the ability of these compounds to overcome ALK resistance can be evaluated.
• a EML4-ALK covalent compound can bind and target the EML4 domain, which can be used, e.g., to potentially overcome ALK resistance.

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