WO2023046060A1 - 治疗kras突变的癌症患者 - Google Patents

治疗kras突变的癌症患者 Download PDF

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WO2023046060A1
WO2023046060A1 PCT/CN2022/120817 CN2022120817W WO2023046060A1 WO 2023046060 A1 WO2023046060 A1 WO 2023046060A1 CN 2022120817 W CN2022120817 W CN 2022120817W WO 2023046060 A1 WO2023046060 A1 WO 2023046060A1
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cancer
kras
mutation
tumor
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WO2023046060A9 (zh
WO2023046060A8 (zh
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段建新
李安蓉
孟繁英
齐天阳
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Ascentawits Pharmaceuticals Ltd
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Priority to EP22872104.9A priority Critical patent/EP4406538A4/en
Priority to JP2024518869A priority patent/JP2024535913A/ja
Priority to CN202280060627.9A priority patent/CN117956998A/zh
Priority to US18/693,111 priority patent/US20250281514A1/en
Priority to KR1020247011060A priority patent/KR20240067907A/ko
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    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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Definitions

  • the present invention relates to a treatment method for cancer, especially a treatment method for cancer patients with KRAS mutation.
  • the full name of the KRAS gene is Kirsten ratsarcoma viral oncogene homolog, translated into Chinese as "Kirsten rat sarcoma virus oncogene homolog".
  • the protein encoded by the KRAS gene is a small GTPase (smallGTPase), which belongs to the RAS superprotein family.
  • the RAS gene includes KRAS, NRAS and HRAS.
  • the proteins encoded by these genes are GTPases, which are in the pathway of regulating cell proliferation and survival function as a molecular switch. Based on current COSMIC data, KRAS was the most frequently mutated gene among the three (22%), followed by NRAS (8%), and lastly HRAS (3%).
  • KRAS gene has a great influence on human cancer, about 30% of cancer patients have KRAS mutation, including 90% of pancreatic cancer, 50% of colon cancer and 25% of lung cancer.
  • KRAS gene mutation accounts for 20-30%, mostly in lung adenocarcinoma, but rare in lung squamous cell carcinoma.
  • KRAS gene mutations are mainly concentrated at the 12th, 13th and 61st codon positions, and the mutations at the 12th codon position account for more than 80%, including G12A, G12C, G12D, G12R, G12S and G12V.
  • KRAS-G12C mutations The most common way of KRAS gene activation is point mutation, and 95% of KRAS mutations mainly occur in codon 12 (>80%) and codon 13 of exon 2.
  • KRAS-G12C mutations 93% of all KRAS mutations
  • Loong HHF, Du N Cheng C, Lin H, Guo J, Lin G, Li M, Jiang T, Shi Z, Cui Y, Jin X, Yao J, Xing Y, Yao M, Wang K, Mok TSK, Liu L.
  • KRAS G12C mutations in Asia A landscape analysis of 11, 951 Chinese tumor samples. Transl Lung Cancer Res 2020. doi: 10.21037/tlcr-20-455).
  • the G12C mutation of the KRAS gene whose mutant has a cysteine residue (glycine at position 12 to cysteine), has been used to design covalent inhibitors with preclinical activity.
  • AMG-510 the first KRAS-G12C inhibitor in clinical development
  • MRTX849 have shown strong anti-tumor activity.
  • Sotorasib (AMG-510, Lumakras), known in the industry as a "revolutionary anticancer drug" effective against KRAS mutations, was approved by the FDA for the treatment of non-small cell lung cancer patients with KRAS-G12C mutations , these patients had received at least one prior systemic therapy.
  • AMG510 is specifically targeting the mutant subtype of KRAS-G12C, with high selectivity, and can specifically bind to, lock and inactivate KRAS-G12C in more than 6,000 proteins.
  • Adagrasib Adagrasib, MRTX849 Breakthrough Therapy Designation for the treatment of non-small cell lung cancer with KRAS-G12C mutations who have previously received systemic therapy (NSCLC) patients.
  • the drug is a specific and optimized oral inhibitor of the KRAS-G12C mutant.
  • MRTX849 is effective in treating non-small cells carrying KRAS-G12C gene mutations It has shown promising safety and anticancer activity in lung cancer (NSCLC) and colorectal cancer (CRC) and other solid tumors.
  • AST-3424 is a first-in-class DNA alkylation cancer therapy targeting overexpressed aldoketone reductase 1C3 (AKR1C3), which can selectively target cancers overexpressing AKR1C3 , and selectively releases a potent DNA alkylating agent in the presence of the AKR1C3 enzyme.
  • This selective mode of activation distinguishes AST-3424 from conventional alkylating agents such as cyclophosphamide and ifosfamide.
  • AKR 1C3 overexpression is present in a variety of treatment-resistant and refractory cancers, including HCC, castration-resistant prostate cancer (CRPC), and T-cell acute lymphoblastic leukemia (T-ALL).
  • AKR1C3 is highly expressed in as many as 15 solid and hematologic tumors.
  • the drug is undergoing phase II clinical trials in China and the United States (US OBI-3424-NCT03592264-II, castrated prostate cancer and liver cancer; US OBI-3424-NCT04315324-II, T-lymphocyte acute leukemia T-ALL; China AST-3424-CTR20191399-II phase, solid tumor; China AST-3424-CTR20201915-II phase, T lymphocyte acute leukemia T-ALL and B lymphocyte acute leukemia B-ALL).
  • AST-3424 Discovery of AST-3424 and compounds in in vivo animal model studies of this drug and similar drugs (hereinafter referred to as AST) has a good therapeutic effect on the KRAS mutant G12D subtype tumor model that highly expresses AKR1C3.
  • the application provides the following methods for treating cancer and pharmaceutical uses of the compounds.
  • a treatment method which uses a drug containing a DNA alkylating agent prodrug compound activated by AKR1C3 as a single drug or in combination with other therapeutic drugs to treat cancer and tumor patients with KRAS mutations.
  • the pharmaceutical application of the DNA alkylating agent prodrug compound activated by AKR1C3, the compound is used for the preparation of a single drug or in combination with other therapeutic drugs to treat cancer and tumor patients with KRAS mutation.
  • the AKR1C3-activated DNA alkylating agent prodrug compound means that the compound is a prodrug, and the prodrug molecule reacts with the AKR1C3 enzyme to release a cytotoxic DNA alkylating agent after the reaction.
  • AST-3424 is taken as an example. These compounds, as specific substrates of aldehyde and ketone reductase AKR1C3, can be quickly and effectively reduced only in cancer cells with high expression of AKR1C3, thereby releasing the cytotoxin-DNA alkylating agent AST-2660, AST-2660 cross-links DNA causing cancer cells to:
  • Therapeutic method uses the drug single drug containing the DNA alkylating agent prodrug compound of AKR1C3 activation or in combination with other therapeutic drugs to treat cancer and tumor patients with KRAS mutation, and the compound is selected from structural formula 1/2 and its salts, esters, solvents compounds, isotopomers:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , R 9 , and R 10 are as described in the claims of patent application PCT/CN2020/089692, publication number WO2020228685A1. details as follows:
  • R 1 is C 6 -C 10 aryl or Z substituted aryl, 4-15 membered heterocycle or Z substituted heterocycle, 5-15 membered heteroaryl or Z substituted heteroaryl, 7-15 membered condensed ring Or Z replaces the fused ring;
  • R2 is hydrogen, halogen atom, cyano or isocyano, hydroxyl, mercapto, amino, OTs, OMS, C 1 -C 6 alkyl or Z substituted alkyl, C 2 -C 6 alkenyl or Z substituted alkenyl C 2 -C 6 alkynyl or Z substituted alkynyl, C 3 -C 8 cycloalkyl or Z substituted cycloalkyl, C 6 -C 10 aryl or Z substituted aryl, 4-15 membered heterocycle or Z-substituted heterocycle, 5-15 membered heteroaryl or Z-substituted heteroaryl, ether with 1-6 carbon atoms or Z-substituted alkoxy with 1-6 carbon atoms, -CONR 6 R 7 , -SO 2NR6R7 , -SO2R6 , -OCOO - R6 , -COOR6 , -NR6COR7 ,
  • R3 is hydrogen, halogen, cyano or isocyano, hydroxyl, mercapto, amino, OTs, OLCMS, C 1 -C 6 alkyl or Z substituted alkyl, C 2 -C 6 alkenyl or Z substituted alkenyl , C 2 -C 6 alkynyl or Z substituted alkynyl, C 3 -C 8 cycloalkyl or Z substituted cycloalkyl, C 6 -C 10 aryl or Z substituted aryl, 4-15 membered heterocycle or Z Substituted heterocycle, 5-15 membered heteroaryl or Z substituted heteroaryl, C 1 -C 6 alkoxy or Z substituted C 1 -C 6 alkoxy, -CONR 6 R 7 , -SO 2 NR 6 R 7 , -SO 2 R 6 , -OCO-R 6 , -OCOO-R 6 , -COOR 6 , -NR 6 COR 7 ,
  • R 4 and R 5 are each independently hydrogen, halogen atom, cyano or isocyano, hydroxyl, mercapto, amino, OTs, OLCMS, C 1 -C 6 alkyl or Z-substituted alkyl, C 2 -C 6 Alkenyl or Z substituted alkenyl, C 2 -C 6 alkynyl or Z substituted alkynyl, C 3 -C 8 cycloalkyl or Z substituted cycloalkyl, C 6 -C 10 aryl or Z substituted aryl, 4 -15-membered heterocycle or Z-substituted heterocycle, 5-15-membered heteroaryl or Z-substituted heteroaryl, C 1 -C 6 alkoxy or Z-substituted C 1 -C 6 alkoxy, -CONR 6 R 7 , -SO 2 NR 6 R 7 , -SO 2 R 6 , -OCOO-R 6 , -COOR
  • R 6 and R 7 are each independently hydrogen, cyano or isocyano, C 1 -C 6 alkyl or Z substituted alkyl, C 2 -C 6 alkenyl or Z substituted alkenyl, C 2 -C 6 alkyne or Z-substituted alkynyl, C 3 -C 8 cycloalkyl or Z-substituted cycloalkyl, C 6 -C 10 aryl or Z-substituted aryl, 4-15 membered heterocycle or Z-substituted heterocycle, 5-15 Elementary heteroaryl or Z-substituted heteroaryl, C 1 -C 6 alkoxy or Z substituted C 1 -C 6 alkoxy, or R 6 , R 7 groups form a 5- 7-membered heterocyclic group or Z-substituted 5-7-membered heterocyclic group;
  • R 8 and R 10 are each independently hydrogen, deuterium, aryl or Z substituted aryl, C 1 -C 6 alkyl or Z substituted alkyl, C 2 -C 6 alkenyl or Z substituted alkenyl, C 2 - C 6 alkynyl or Z substituted alkynyl, C 3 -C 8 cycloalkyl or Z substituted cycloalkyl, and one of them must be hydrogen or deuterium;
  • R 9 is a substituted C 6 -C 10 aryl group having at least one fluorine atom or a nitro group, a substituted 4-15 membered heterocycle having at least one fluorine atom or a nitro group, a substituted 4-15 membered heterocycle having at least one fluorine atom or a nitro group Substitute 5-15 membered heteroaryl.
  • Z substituent is halogen atom, cyano or isocyano, hydroxyl, mercapto, amino, OTs, OMS, C 1 -C 3 alkyl or substituted alkyl, C 1 -C 3 alkoxy or substituted alkoxy , C 2 -C 3 alkenyl or substituted alkenyl, C 2 -C 3 alkynyl or substituted alkynyl, C 3 -C 8 cycloalkyl or substituted cycloalkyl, aromatic ring, heterocyclic ring, heteroaryl ring and fused Ring or substituted aromatic rings, heterocyclic rings, heteroaryl rings and condensed rings, the substitution mode is mono-substitution or gem-di-substitution;
  • Substituted C 6 -C 10 aryl, substituted 4-15 membered heterocyclic, substituted 5-15 membered heteroaryl in R 9 are halogen atom, nitro, cyano or isocyano, hydroxyl, amino , C 1 -C 3 alkyl or alkoxy, alkenyl, alkynyl, cycloalkyl or benzene ring, substituted benzene ring, C 1 -C 3 alkoxy or halogen atom substituted alkoxy.
  • the compound of formula (1) (2) is selected from:
  • the compound of structural formula 1/2 is the same as AST-3424 and AST, both of which are prodrugs of AST-2660, which will be activated under the action of AKR1C3 enzyme to produce AST-2660 (a DNA alkylating agent) to exert anticancer effect :
  • Therapeutic method uses the drug single drug containing the DNA alkylating agent prodrug compound of AKR1C3 activation or in combination with other therapeutic drugs to treat cancer and tumor patients with KRAS mutation, the compound is selected from structural formula 3 and its salts, esters, solvates , Isotopic isomers:
  • A is H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, CFH 2 , CF 2 H, CF 3 , F, Cl, Br, I, OCF 3 , COR or CON(R) 2 ;
  • E is SO or SO2 ;
  • X is Cl, Br, I or OSO 2 R;
  • Y is Cl, Br, I or OSO 2 R;
  • Each R is independently H or C1-C6 alkyl
  • G is a free radical selected from the group comprising formulas (B)-(AA):
  • R1 is H, C1-C6 alkyl, CH2 ( CH2 )nOH, CH2CH (OH) CH2OH , phenyl, pyridyl, benzyl or pyridylmethyl, provided that when R1 is benzene
  • R 2 and R 3 are each independently H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, OR 6 , N(R 6 )(R 7 ), CFH 2 , CF 2 H, CF 3 , F, Cl, Br, I, OCF 3 , COR 6 , CON(R 6 )(R 7 ), SOR 6 , SON(R 6 )(R 7 ), SO2R 6 , SO2N(R 6 )(R 7 ), CN or NO 2 ;
  • R 4 is N(R 6 )(R 7 ), OH, OCH 2 (CH 2 )nN(R 6 )(R 7 ) or CH 2 (CH 2 )nN(R 6 )(R 7 );
  • R 5 is H or C1-C6 alkyl group
  • R 6 and R 7 are each independently H or C1-6 alkyl, or R 6 and R 7 together form a substituted or unsubstituted 5-membered or 6-membered heterocyclic ring:
  • Z is CH or N
  • W is CH2 , O, S, SO or SO2 ;
  • n 0 to 6;
  • the compound of formula (3) is selected from:
  • the compound of structural formula 3 is similar to AST-3424 and AST in principle, and they are all nitrogen mustard analogs Prodrugs of , which are activated by the enzyme AKR1C3 to produce nitrogen mustard analogs (a DNA alkylating agent) exerts anticancer effect:
  • Therapeutic method uses the drug containing the DNA alkylating agent prodrug compound containing AKR1C3 activation to treat cancer and tumor patients with KRAS mutation as a single drug or in combination with other therapeutic drugs.
  • the compound is selected from structural formula 4 and its salts, esters, and solvates Compounds, isotopomers:
  • R 1 is H, C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl or phenyl, wherein said C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl are optionally substituted by 1, 2 or 3 R a ;
  • Each R is independently H, F, Cl, Br, I, -CN, -OH, C 1-3 alkoxy or C 1-3 alkyl;
  • R 2 is H or C 1-6 alkyl
  • R1 and R2 are joined together to form a 4-6 membered heterocycloalkyl group together with the N atom to which they are attached, wherein the 4-6 membered heterocycloalkyl group is optionally substituted by 1, 2 or 3 R b ;
  • each R is independently H, F, Cl, Br, I, -CN, -OH, -NH2 , -OCH3 , -OCH2CH3 , -CH3 , or -CH2CH3 ;
  • R 3 is H, F, Cl, Br, I, -OH, -NH 2 , C 1-3 alkoxy or C 1-3 alkyl;
  • T 1 is -(CR c R d ) m -or -(CR c R d ) n -O-;
  • n 1, 2 or 3;
  • n 1 or 2;
  • T2 is N or CH
  • R c and R d are each independently H, F, C 1-3 alkyl or C 1-3 alkoxy;
  • R 4 , R 5 and R 6 are each independently H, F, Cl, Br, I, C 1-3 alkyl or C 1-3 alkoxy;
  • T is N or CH
  • R 7 and R 8 are each independently H, F, Cl, Br or I;
  • R 9 and R 10 are each independently H, F, Cl, Br, I, -CN or
  • the 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl each contain 1, 2, 3 or 4 heteroatoms independently selected from N, -O- and -S-.
  • the compound of formula (4) is selected from:
  • the compound of structural formula 3 is the same as AST-3424 and AST, both of which are prodrugs of AST-2660, which will be activated under the action of AKR1C3 enzyme to produce AST-2660 (a DNA alkylating agent) to exert anticancer effect:
  • Therapeutic method uses the drug containing the DNA alkylating agent prodrug compound containing AKR1C3 activation as a single drug or in combination with other therapeutic drugs to treat cancer and tumor patients with KRAS mutation, the compound is selected from structural formula 5 and its salts, esters, solvates Compounds, isotopomers:
  • X 10 is O, S, SO or SO 2 ;
  • R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4-15 membered heterocycle, ether, -CONR 13 R 14 or -NR 13 COR 14 ;
  • X, Y and Z are each independently hydrogen, CN, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4-15 membered heterocycle, ether, -CONR 13 R 14 or -NR 13 COR 14 ;
  • R is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4-15 membered hetero Ring, ether, -CONR 13 R 14 or -NR 13 COR 14 ;
  • R 13 and R 14 are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4-15 membered heterocycle or ether
  • T comprises a phosphoramidate alkylating agent comprising one or more Z5- X5 - Y5 moieties bonded to an -OP( Z1 ) moiety, wherein Z5 is a heteroatom containing nitrogen, sulfur or oxygen, X5 is substituted or unsubstituted ethylidene, Y5 is halo or another leaving group, or Z5 - X5 - Y5 together form an aziridinyl (NCH 2 CH 2 ) moiety and Z 1 is O or S; and
  • alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, ether groups are substituted or unsubstituted.
  • the compound of formula (5) is selected from:
  • the compound of structural formula 5 is similar to AST-3424 and AST, and is a prodrug of phosphoramidate alkylating agent, which will be activated under the action of AKR1C3 enzyme to produce T (a phosphoramidate alkylating agent, AST- 2660 is a phosphoramidate alkylating agent) to exert anti-cancer effects:
  • Therapeutic method uses the drug containing the DNA alkylating agent prodrug compound containing AKR1C3 activation as a single drug or in combination with other therapeutic drugs to treat cancer and tumor patients with KRAS mutation, the compound is selected from structural formula 6 and its salts, esters, solvates Compounds, isotopomers:
  • R 100 , R 101 and R 102 are each independently hydrogen, C1-C8 alkyl, C6-C12 aryl; or R 101 and R 102 form a 5-7 membered heterocyclic ring together with the nitrogen atom to which they are attached;
  • alkyl group and the aryl group are each substituted by 1-3 halo groups or 1-3 C1-C6 alkyl groups;
  • R 1 and R 2 are each independently phenyl or methyl
  • X, Y, and Z are each independently hydrogen or halo
  • R is hydrogen or C1-C6 alkyl or halogen-substituted alkyl.
  • Compound also of course includes the compound itself as well as the solvate, salt, ester or isotope of the compound and the like.
  • Cx-Cy or " Cxy " before a group refers to the range of the number of carbon atoms present in the group.
  • C1-C6 alkyl refers to an alkyl group having at least 1 and at most 6 carbon atoms.
  • Alkyl means a monovalent saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms, and in some embodiments 1 to 6 carbon atoms.
  • Cy-y alkyl refers to an alkyl group having x to y carbon atoms.
  • the term includes, for example, straight chain and branched chain hydrocarbon groups such as methyl ( CH3- ), ethyl ( CH3CH2- ), n- propyl ( CH3CH2CH2- ), isopropyl group ((CH 3 ) 2 CH-), n-butyl group (CH 3 CH 2 CH 2 CH 2 -), isobutyl group ((CH 3 ) 2 CHCH 2 -), sec-butyl group ((CH 3 )(CH 3 CH 2 )CH-), tert-butyl ((CH 3 ) 3 C-), n-pentyl (CH 3 CH 2 CH 2 CH 2 CH 2 - ) and neopentyl ((CH 3 ) 3 CCH 2 - ).
  • straight chain and branched chain hydrocarbon groups such as methyl ( CH3- ), ethyl ( CH3CH2- ), n- propyl ( CH3CH2CH2- ), isopropyl group ((CH 3 ) 2 CH
  • Aryl means an aromatic group having from 6 to 14 carbon atoms and containing no ring heteroatoms and having a single ring (for example, phenyl) or multiple condensed (fused) rings (for example, naphthyl or anthracenyl). group.
  • aryl is used when the point of attachment is at an aromatic carbon atom or "Ar” is suitable (eg, 5,6,7,8 tetrahydronaphthalen-2-yl is aryl because its point of attachment is at the 2 position of the aromatic phenyl ring).
  • Arylenyl refers to a divalent aryl group having an appropriate hydrogen content.
  • Cycloalkyl means a saturated or partially saturated cyclic group having from 3 to 14 carbon atoms and no ring heteroatoms and having a single ring or multiple rings including fused, bridged and spiro ring systems.
  • cycloalkyl applies when the point of attachment is at a non-aromatic carbon atom (e.g. 5, 6, 7, 8-tetrahydronaphthalen-5-yl).
  • cycloalkyl includes cycloalkenyl groups.
  • cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and cyclohexenyl.
  • Cycloalkylene refers to a divalent cycloalkyl group having an appropriate hydrogen content.
  • Halo refers to one or more of fluorine, chlorine, bromine and iodine.
  • Heteroaryl means an aromatic group having 1 to 14 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur and includes monocyclic rings such as imidazolyl-2-yl and imidazol-5-yl) and polycyclic systems (eg imidazopyridinyl, benzotriazolyl, benzimidazol-2-yl and benzimidazol-6-yl).
  • monocyclic rings such as imidazolyl-2-yl and imidazol-5-yl
  • polycyclic systems eg imidazopyridinyl, benzotriazolyl, benzimidazol-2-yl and benzimidazol-6-yl.
  • heteroaryl such as 1,2,3,4-tetrahydroquinolin-6-yl and 5,6,7,8-tetrahydroquinolin-3-yl.
  • the nitrogen and/or sulfur ring atoms of the heteroaryl are optionally oxidized to provide an N-oxide (N ⁇ O), sulfinyl or sulfonyl moiety.
  • heteroaryl includes, but is not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuryl, benzothiofuryl, benzothiophenyl, benzoxa Azolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzothienyl, benzimidazolyl, carbazolyl , NH-carbazolyl, carbolinyl, chromanyl (chromanyl), benzopyranyl (chromenyl), cinnolinyl (cinnolinyl), dithiazinyl, furyl, furyl, Imidazolidinyl
  • Heterocyclic or “heterocycle” or “heterocycloalkyl” or “heterocyclyl” means a heteroatom having 1 to 14 carbon atoms and 1 to 6 selected from the group consisting of nitrogen, sulfur or oxygen and include monocyclic and polycyclic ring systems including fused, bridged and spiro ring systems.
  • heterocyclic For polycyclic ring systems having aromatic and/or non-aromatic rings, the terms “heterocyclic”, “heterocyclic” when at least one ring heteroatom is present and the point of attachment is at an atom of the non-aromatic ring , “heterocycloalkyl” or “heterocyclyl” are suitable (such as 1,2,3,4-tetrahydroquinolin-3-yl, 5,6,7,8-tetrahydroquinolin-6-yl and decahydroquinolin-6-yl).
  • the heterocyclyl group herein is a 3-15 membered, 4-14 membered, 5-13 membered, 7-12 or 5-7 membered heterocyclic ring.
  • the heterocycle contains 4 heteroatoms. In some other embodiments, the heterocycle contains 3 heteroatoms. In another embodiment, the heterocycle contains up to 2 heteroatoms. In some embodiments, the nitrogen and/or sulfur atoms of the heterocyclyl are optionally oxidized to provide N-oxide, sulfinyl, sulfonyl moieties.
  • Heterocyclic groups include, but are not limited to, tetrahydropyranyl, hexahydropyridinyl, N-methylhexahydropyridin-3-yl, hexahydropyrazinyl, N-methylpyrrolidin-3-yl, 3 -pyrrolidinyl, 2-pyrrolidinon-1-yl, morpholinyl and pyrrolidinyl.
  • a prefix indicating the number of carbon atoms (eg, C3-10) refers to the total number of carbon atoms in the heterocyclyl moiety excluding the number of heteroatoms.
  • Divalent heterocyclic groups will have suitably adjusted hydrogen content.
  • Biaryl refers to a structure in which two aromatic rings are connected through a C-C single bond, such as biphenyl, bipyridine, etc.
  • a group may be substituted with one or more substituents (eg 1 , 2, 3, 4 or 5 substituents).
  • the substituent is selected from the group consisting of chlorine, fluorine, -OCH 3 , methyl, ethyl, isopropyl, cyclopropyl, -CO 2 H and its salts, and C 1 -C 6 alkyl Esters, CONMe 2 , CONHMe, CONH 2 , -SO 2 Me, -SO 2 NH 2 , -SO 2 NMe 2 , -SO 2 NHMe, -NHSO 2 Me, -NHSO 2 CF 3 , -NHSO 2 CH 2 Cl, -NH 2 , -OCF 3 , -F 3 and -OCHF 2 .
  • the compound of formula (6) is selected from:
  • the compound of structural formula 6 is similar to AST-3424 and AST, and is a prodrug of AST-2660, which will be activated under the action of AKR1C3 enzyme to produce AST-2660 to exert anticancer effect:
  • AST-3424 (OBI-3424), (hereinafter code-named AST) and The synthesis method and spectral data of the patent application: PCT/US2016/021581, publication number WO2016145092A1, corresponding to Chinese application number 2016800150788, publication number CN107530556A; PCT/US2016/062114, publication number WO2017087428A1, corresponding to Chinese application number 2016800200101A, publication PCT/CN2020/089692, disclosed by publication number WO2020228686; related preparations concentrated injections, and related prescriptions, preparation methods, clinical compatibility, and administration methods are described and disclosed in detail by related patents: WO2021008520A1, WO2021043275A1, and the present invention combines the above The full text of the application text is incorporated.
  • Monotherapy that is, monotherapy.
  • Combined use that is, combined drug therapy.
  • Monotherapy refers to the use of only one anticancer drug in a course of treatment.
  • Combination therapy refers to the simultaneous or successive use of two or more anticancer drugs in one course of treatment.
  • combination therapy needs to explore different dosages and administration cycles according to the characteristics of the disease and the types of drugs used in combination. Only based on the above conditions can the combination drug treatment plan obtained through exploration be able to achieve better therapeutic effects than single drug therapy.
  • the drug dosage and dosage cycle of single drug and combined therapy need to be obtained through clinical trials with reference to the dosage and dosage of AST-3424 and its similar compounds and other drugs mentioned above.
  • the dosage of a single drug can be determined by referring to the animal experiment doses of WO2019062919A1, WO2016145092A1, and WO2017087428A1.
  • the KRAS mutation is selected from KRAS-G12D mutation, KRAS-G12V mutation and KRAS-G12C mutation.
  • Any one or two gene mutations in the genes corresponding to KRAS can be detected and diagnosed by commercially available (accompanied) diagnostic kits, such as the diagnostic kits approved in China:
  • NGS sequencing (YS 450 gene NGS large panel) can also be used to determine the specific KRAS mutation subtype.
  • the KRAS mutation is selected from the KRAS-G12D mutation.
  • the TMB (Tumor Mutation Burden) level of the gene mutation is moderate.
  • TMB Tumor mutation load (burden), that is, tumor gene mutation load
  • burden Tumor mutation load
  • Mb represents every million bases
  • CheckMate-032 This is a Phase II clinical trial of 401 advanced lung cancer patients who failed first-line treatment, receiving PD-1 inhibitors alone or in combination with Yipimu.
  • TMB Tumor mutation load
  • the effective rates of the three groups are 62%, 20%, and 23%, respectively, and the effective rate of the high TMB group is 3 times; and the median overall survival of the three groups were: 22.0 months, 3.6 months, 3.4 months - 22.0 months and 3.4 months, a difference of 6 times!
  • prodrug compound is preferably selected from:
  • the aforementioned cancer is selected from ovarian cancer, breast cancer, pancreatic cancer, fallopian tube cancer, primary peritoneal cancer, gastric cancer, prostate cancer, liver cancer, colon cancer, rectal cancer, lung cancer, bladder cancer.
  • Other therapeutic drugs are selected from KRAS inhibitors, immunotherapeutic drugs (immune checkpoint inhibitors).
  • KRAS inhibitors are substances that inhibit the enzymatic activity of KRAS.
  • KRAS inhibitors please refer to the review literature Goebel, Lisa&Müller, Matthias&Goody, Roger&Rauh, Daniel.(2020).KRasG12C inhibitors in clinical trials: A short historical perspective.RSC Medicinal Chemistry.11.10.1039/D0MD00096E.
  • KRAS inhibitors that have entered clinical development or are already on the market include Sotorasib (AMG510) developed by Amgen, adagrasib (MRTX849) developed by Mirati Therapeutics, GDC6036 developed by Roche, LY3499446 developed by Eli Lilly, JNJ74699157 (ARS3248) jointly developed by Araxes and Janssen ), D-1553 developed by Inventio, JAB-3312 developed by JACOS, JAB-3068 developed by JACOS, GH35 developed by Gen House, BPI-421286 developed by Betta Pharmaceuticals, BI17016963 developed by Boehringer Ingelheim, mRNA-5671 developed by Moderna, and AZD-4785 jointly developed by AstraZeneca and Ionis.
  • Sotorasib AMG510
  • MRTX849 adagrasib
  • Mirati Therapeutics GDC6036 developed by Roche
  • LY3499446 developed by Eli Lilly
  • the KRAS inhibitor is selected from Sotorasib (AMG510), adagrasib (MRTX849), GDC6036, LY3499446, JNJ74699157 (ARS3248), D-1553;
  • Immune checkpoint molecules are inhibitory regulatory molecules in the immune system that are critical for maintaining self-tolerance, preventing autoimmune responses, and minimizing tissue damage by controlling the timing and intensity of immune responses .
  • Immune checkpoint molecules are expressed on immune cells, which will inhibit the function of immune cells, so that the body cannot produce effective anti-tumor immune responses, and tumors form immune escape.
  • the tumor-related immune checkpoint molecules mainly include: PD1, PD-L1, CTLA4, Tim3, and LAG3, etc.
  • PD1, PD-L1, and CTLA4 are the most studied.
  • Immune checkpoint inhibitors are some monoclonal antibody drugs developed for the corresponding immune checkpoints. inhibition. Immunotherapy drugs are selected from PD-1 monoclonal antibody and PD-L1 monoclonal antibody.
  • the cancer and tumor are preferably selected from gastric cancer, pancreatic cancer, and lung cancer.
  • the above-mentioned medicines should also add pharmaceutically acceptable auxiliary materials or excipients according to the specificity of medicines, medicines and preparations.
  • the medicine can be in any dosage form for clinical application, such as tablet, suppository, dispersible tablet, enteric-coated tablet, chewable tablet, orally disintegrating tablet, capsule, sugar-coated agent, granule, dry powder, oral solution, small needle for injection , Freeze-dried powder for injection or large infusion.
  • the pharmaceutically acceptable adjuvant or excipient in the medicine may include one or more of the following: diluent, solubilizer, disintegrant, suspending agent, lubricant, viscose Mixtures, fillers, flavoring agents, sweeteners, antioxidants, surfactants, preservatives, coating agents, and pigments, etc.
  • Figure 1 is Growth curves of tumor volume in each group of mice in the gastric cancer GA6201 model
  • Figure 2 is Relative tumor inhibition rate curves of mice in each group in the gastric cancer GA6201 model
  • Figure 3 is Body weight curves of mice in each group in the gastric cancer GA6201 model
  • Figure 4 is Body weight change percentage curves of mice in each group in the gastric cancer GA6201 model
  • Figure 5 is Growth curves of tumor volume in each group of mice in the pancreatic cancer PA1222 model
  • Figure 6 is The relative tumor inhibition rate of mice in each group in the pancreatic cancer PA1222 model
  • Figure 7 is Body weight curves of mice in each group in the pancreatic cancer PA1222 model
  • Figure 8 is Body weight change percentage curves of mice in each group in the pancreatic cancer PA1222 model
  • Figure 9 is The growth curves of the tumor volume of mice in each group in the lung cancer LU11693 model.
  • Figure 10 is Relative tumor inhibition rate curves of mice in each group in the lung cancer LU11693 model
  • Figure 11 is Body weight curves of mice in each group in the lung cancer LU11693 model
  • Figure 12 is Body weight change percentage curves of mice in each group in the lung cancer LU11693 model
  • Figure 13 is the tumor volume growth curves of mice in each group in the subcutaneous xenograft model of human pancreatic cancer HPAF-II;
  • Fig. 14 is the percentage change curve of mouse body weight in each group in the subcutaneous xenograft model of human-derived pancreatic cancer HPAF-II;
  • Figure 15 is Tumor volume growth curves of mice in each group in the subcutaneous model of lung cancer LU5161;
  • Figure 16 is Body weight change percentage curves of mice in each group in the lung cancer LU5161 subcutaneous model
  • Figure 17 is Tumor volume growth curves of mice in each group in the colon cancer CR3820 subcutaneous model
  • Figure 18 is Body weight change percentage curves of mice in each group in the intestinal cancer CR3820 subcutaneous model
  • Figure 19 is Tumor volume growth curves of mice in each group in the subcutaneous model of pancreatic cancer PA2637;
  • Figure 20 is Body weight change percentage curves of mice in each group in the pancreatic cancer PA2637 subcutaneous model
  • Figure 21 is Tumor volume growth curves of mice in each group in the subcutaneous model of lung cancer LU11873;
  • Figure 22 is Body weight change percentage curves of mice in each group in the lung cancer LU11873 subcutaneous model
  • Figure 23 is Tumor volume growth curves of mice in each group in the subcutaneous model of pancreatic cancer PA1383;
  • Figure 24 is Body weight change percentage curves of mice in each group in the pancreatic cancer PA1383 subcutaneous model
  • Figure 25 is a photo of the IHC staining results of GA6201, LU11693, PA1222 models and the control group.
  • administering or “administration of” a drug (and grammatical equivalents of this phrase) to a patient means direct administration (which may be administered to the patient by a medical professional or may be self-administered) and/or indirect administration, It is the act of prescribing a drug.
  • direct administration which may be administered to the patient by a medical professional or may be self-administered
  • indirect administration It is the act of prescribing a drug.
  • a physician who instructs a patient to self-administer a drug and/or provides a prescription for the drug to the patient is administering the drug to the patient.
  • Cancer refers to leukemias, lymphomas, carcinomas and other malignancies (including solid tumors) of potentially unrestricted growth that can spread locally by invasion and systemically by metastasis.
  • cancers include, but are not limited to, adrenal, bone, brain, breast, bronchi, colon and/or rectum, gallbladder, head and neck, kidney, larynx, liver, lung, nervous tissue, pancreas, prostate, parathyroid, Cancers of the skin, stomach and thyroid.
  • cancers include acute and chronic lymphocytic and granulocytic neoplasms, adenocarcinoma, adenoma, basal cell carcinoma, cervical dysplasia and carcinoma in situ, Ewing's sarcoma, epidermoid carcinoma, giant Cytoma, glioblastoma multiforme, hair cell tumor, enteric ganglioneuroma, hyperplastic corneal neuroma, islet cell carcinoma, Kaposi's sarcoma, leiomyoma, leukemia, lymphoma, Malignant carcinoid tumor, malignant melanoma, malignant hypercalcemia, marfanoid habitus tumor, medullary epithelial carcinoma, metastatic skin cancer, mucosal neuroma, myeloma, mycosis fungoides, neuroderm Cytoma, osteosarcoma, osteogenic and other sarcomas, ovarian tumors, pheochromocytoma,
  • a patient and “individual” are used interchangeably and refer to a mammal in need of cancer treatment.
  • the patient is a human.
  • the patient is a human being diagnosed with cancer.
  • a "patient” or “individual” may refer to a non-human mammal, such as a non-human primate, dog, cat, rabbit, pig, mouse, for screening, characterization and evaluation of drugs and therapies or rats.
  • Solid tumor refers to solid tumors including, but not limited to, metastatic tumors in bone, brain, liver, lung, lymph nodes, pancreas, prostate, skin, and soft tissue (sarcomas).
  • a "therapeutically effective amount" of a drug is that amount of a drug that, when administered to a patient with cancer, will have the desired therapeutic effect (eg, alleviation, amelioration, remission, or elimination of the clinical manifestations of one or more cancers in the patient) .
  • a therapeutic effect does not necessarily occur through administration of one dose, and may only occur after administration of a series of doses. Thus, a therapeutically effective amount can be administered in one or more administrations.
  • Treating means taking steps to obtain a beneficial or desired result (including a clinical result).
  • beneficial or desired clinical outcomes include, but are not limited to, alleviation or amelioration of one or more symptoms of cancer; reduction in extent of disease; delay or slowing of disease progression; amelioration, remission or stabilization of disease state; or other beneficial outcomes.
  • treatment of cancer can result in a partial response or stable disease.
  • Tumor cell refers to a tumor cell of any appropriate species (eg, a mammal such as murine, canine, feline, equine or human).
  • a patient and “individual” are used interchangeably and refer to a mammal in need of cancer treatment.
  • the patient is a human.
  • the patient is a human being diagnosed with cancer.
  • a "patient” or “individual” may refer to a non-human mammal, such as a non-human primate, dog, cat, rabbit, pig, mouse, for screening, characterization and evaluation of drugs and therapies or rats.
  • Treating or “treating a patient” refers to administering, using or administering to a patient a therapeutically effective amount of a drug relevant to the present invention.
  • administering or “administering” "using" a drug to a patient refers to direct administration or administration (which may be administered or administered to the patient by a medical professional or may be self-administered or administered) and/or indirect administration or administration, which may prescribe the drug the behavior of.
  • direct administration or administration which may be administered or administered to the patient by a medical professional or may be self-administered or administered
  • indirect administration or administration which may prescribe the drug the behavior of.
  • a physician who instructs a patient to self-administer or administer a drug and/or provides a prescription for the drug to the patient is administering or administering the drug to the patient.
  • Treatment of a condition or patient refers to steps taken to obtain beneficial or desired results (including clinical results).
  • beneficial or desired clinical outcomes include, but are not limited to, alleviation or amelioration of one or more symptoms of cancer; reduction in extent of disease; delay or slowing of disease progression; amelioration, remission or stabilization of disease state; or other beneficial outcomes.
  • treatment of cancer can result in a partial response or stable disease.
  • test substances AST, AST-3424 and Ifosfamide were in Pharmacodynamic evaluation in subcutaneous xenograft model of gastric cancer GA6201
  • Gastric cancer GA6201 PDX model is a model of KRAS pathogenic mutation (KRAS-G12D) with G12D amino acid mutation.
  • BALB/c nude mice were inoculated subcutaneously
  • the model GA6201 tumor mass was used to establish a subcutaneous transplanted tumor model of human gastric cancer.
  • the test was divided into test drug Ifosfamide (ifosfamide) 60mg/kg group, test drug AST-3424 5mg/kg group, AST 2.5mg/kg and 5mg/kg groups and normal saline (pH 7.0-7.6) vehicle control group, A total of 5 groups, 5 mice in each group.
  • the normal saline (pH 7.0-7.6) vehicle control group, the test drug AST-3424 5mg/kg, AST 2.5mg/kg and 5mg/kg groups were given by tail vein injection, administered once a week, and administered three times in total. Week, look around.
  • the Ifosfamide 60mg/kg group was administered by intraperitoneal injection, five consecutive days a week and two days off, for a total of two weeks of administration, and five weeks of observation.
  • the curative effect is evaluated according to the relative tumor inhibition rate TGI (%), and the safety evaluation is carried out according to the animal body weight change and death.
  • Table 1 Different doses of test drugs in Experimental design of antitumor effect in gastric cancer GA6201 tumor model
  • mice The tumor volumes of mice in different groups were measured on different days, and the average values were obtained. The results are shown in Table 2 below.
  • Table 2 In Changes of tumor volume of mice in each group with treatment time in gastric cancer GA6201 model
  • T/C% is the percentage value of the relative tumor volume or tumor weight between the treatment group and the control group at a certain time point. Calculated as follows:
  • T and C are the average relative tumor volume (RTV) of the treatment group and the control group at a specific time point, respectively.
  • Table 4 The relative tumor inhibition rate of tumors in each group in the gastric cancer GA6201 model
  • Figure 2 can be obtained by making the above table 4 as a graph.
  • mice The body weights of mice in different groups were measured on different days, and the average values were obtained. The results are shown in Table 5 below.
  • Table 6 The percentage of body weight change of mice with different inoculation days in gastric cancer GA6201 model (%Group Mean
  • Group01, Group02, Group03, Group04, and Group05 in Table 4/5/6 are the above-mentioned Group 1, Group 2, Group 3, Group 4, Group 5, and Group 6.
  • 0/1/2/3/4/7/8/9/10/11/14/15/16/17/18/21/24/28/31/35/38 is the number of days after vaccination.
  • test drug AST-3424 was at a dose of 5 mg/kg, and the test drug AST was at a dose of 2.5 mg/kg and 5 mg/kg.
  • Gastric cancer GA6201 has a significant inhibitory effect on tumor growth, and there are statistically significant differences compared with the control group.
  • Test drug Ifosfamide at a dose of 60mg/kg, on Gastric cancer GA6201 has a certain effect of inhibiting tumor growth, but there is no statistically significant difference compared with the control group.
  • test substances AST and Gemcitabine were in Pharmacodynamics and safety evaluation in subcutaneous xenograft model of pancreatic cancer PA1222
  • the PA1222 PDX model of pancreatic cancer is a model of a KRAS pathogenic mutation with a G12D amino acid mutation (KRAS-G12D).
  • BALB/c nude mice were inoculated subcutaneously
  • the model PA1222 tumor mass was used to establish a subcutaneous transplanted tumor model of human pancreatic cancer.
  • the test was divided into test drug Gemcitabine (gemcitabine) 120mg/kg group, test drug AST 10mg/kg and 7.5% absolute ethanol + 7.5% polyoxyethylene (35) castor oil + 85% glucose injection D5W (pH7.4) vehicle Control group, 3 groups in total, 5 mice in each group.
  • test drug AST 10mg/kg group are tail vein injection administration, every week Administration once, continuous administration for three weeks.
  • the test drug Gemcitabine 120mg/kg group was administered by intraperitoneal injection once a week for 3 consecutive weeks.
  • the curative effect is evaluated according to the relative tumor inhibition rate TGI (%), and the safety evaluation is carried out according to the animal body weight change and death.
  • the administration volume is 10 ⁇ l/g
  • mice The tumor volumes of mice in different groups were measured on different days, and the average values were obtained. The results are shown in Table 8 below.
  • Table 8 Changes of tumor volume of mice in each group with treatment time in PA1222 model of pancreatic cancer
  • Table 9 Drug efficacy analysis table of each group in gastric cancer GA6201 model
  • T/C% Relative tumor proliferation rate
  • T and C are the average relative tumor volume (RTV) of the treatment group and the control group at a specific time point, respectively.
  • Table 10 The relative tumor inhibition rate of each group of tumors in the pancreatic cancer PA1222 model
  • mice The body weights of mice in different groups were measured on different days, and the average values were obtained. The results are shown in Table 11 below.
  • Table 11 Body weight of mice with different inoculation days in PA1222 model of pancreatic cancer
  • Test drug Gemcitabine at 120mg/kg (Group 2) dose, on Pancreatic cancer PA1222 has a certain inhibitory effect on tumor growth, and there is a statistically significant difference compared with the control group.
  • Test drug AST at 10mg/kg (Group 3) dose, on Pancreatic cancer PA1222 has a significant tumor inhibitory effect, which is statistically significantly different from that in the control group, and two mice in this group were cured, with a cure rate of 40%.
  • mice in the test drug Gemcitabine (120mg/kg, Group 2) treatment group, AST 10mg/kg (Group 3) treatment group, and control group (Group 1) did not have any significant weight loss. Well tolerated.
  • test substances AST and Cisplatin are in Pharmacodynamics and safety evaluation in subcutaneous xenograft model of lung cancer LU11693
  • the lung cancer LU11693 PDX model is a model of KRAS pathogenic mutations with G12C amino acid mutations.
  • BALB/c Nude nude mice subcutaneously inoculated
  • the model LU11693 tumor mass was used to establish a subcutaneous transplanted tumor model of human lung cancer.
  • the test was divided into test drug Cisplatin 4mg/kg group, test drug AST 10mg/kg group and 7.5% absolute ethanol + 7.5% polyoxyethylene (35) castor oil + 85% glucose injection D5W (pH7.4) vehicle control group , a total of 3 groups, 6 mice in each group, administered by tail vein injection, administered once a week, for 3 consecutive weeks.
  • the curative effect is evaluated according to the relative tumor inhibition rate TGI (%), and the safety evaluation is carried out according to the animal body weight change and death.
  • Table 13 Different doses of test drugs in Experimental design of antitumor effect in lung cancer LU11693 PDX tumor model
  • the administration volume is 10 ⁇ l/g
  • mice The tumor volumes of mice in different groups were measured on different days, and the average values were obtained. The results are shown in Table 14 below.
  • Table 14 Changes of tumor volume of mice in each group with treatment time in lung cancer LU11693 model
  • Table 15 Drug efficacy analysis table of each group in lung cancer LU11693 model
  • the relative tumor proliferation rate, T/C% is the percentage value of the relative tumor volume or tumor weight between the treatment group and the control group at a certain time point. Calculated as follows:
  • T and C are the average relative tumor volume (RTV) of the treatment group and the control group at a specific time point, respectively.
  • Table 16 The relative tumor inhibition rate of each group of tumors in the lung cancer LU11693 model
  • mice The body weights of mice in different groups were measured on different days, and the average values were obtained. The results are shown in Table 17 below.
  • Table 17 Body weight of mice with different inoculation days in lung cancer LU11693 model
  • the rate TGI (%) was 23.98%.
  • test drug AST (10mg/kg) treatment group showed a certain tumor inhibitory effect on the 28th day (Day 28) after the first administration, and there was a statistically significant difference compared with the control group (p ⁇ 0.001).
  • the inhibition rate TGI (%) is 54.64%, TGI is less than 60%, and there is no obvious tumor inhibitory effect.
  • mice in the test drug AST (10 mg/kg) and Cisplatin (4 mg/kg) treatment groups experienced severe weight loss, which may be related to the potential toxicity of high-dose drugs.
  • AST-3424 and AST have significant efficacy in KRAS pathogenic mutation models with G12D amino acid mutation: gastric cancer GA6021 and pancreatic cancer PA1222 PDX models, with TGI% greater than 90%;
  • AST in the KRAS pathogenic mutation model with G12C amino acid mutation the tumor inhibitory effect in lung cancer LU11693 is not obvious, and the TGI% is less than 60%;
  • AST-3424 and AST have generally significant curative effects on various cancer indications.
  • the curative effect of AST is not only related to the cancer type, but also related to other factors.
  • the human pancreatic cancer HPAF-II subcutaneous xenograft model is a CDX model with a KRAS G12D pathogenic mutation.
  • mice were subcutaneously inoculated with human pancreatic cancer HPAF-II cells to establish a subcutaneous transplantation model of human pancreatic cancer.
  • the test is divided into test drug treatment groups: Ifosfamide 60mg/kg single drug group (Group 2) is intraperitoneally administered once a day for 5 consecutive days, rested for 2 days, and then administered once a day for continuous administration 5 days; AST 4mg/kg single-drug group (Group 3) was given tail vein administration once a day for 5 consecutive days, rested for 2 days, rested for another 2 weeks, and administered once a day for continuous administration AST-3424 1 mg/kg single drug group (Group 4) was administered via tail vein once a week for 3 weeks in total; AST-3424 1 mg/kg single drug group (Group 5) was administered via tail vein Administration, administration once a day, continuous administration for 5 days, rest for 2 days, rest for 2 weeks, administration once a day, continuous administration for 5 days; and glucose injection (pH7.7-8.0
  • Table 19 Administration routes, doses and regimens in human-derived pancreatic cancer HPAF-II animal models
  • the abbreviations related to the route of administration i.v. means tail vein injection, i.p. , QD*5" means administer once a day for 5 consecutive days, rest for 2 days, rest for 2 weeks, and then administer once a day for 5 consecutive days.
  • the tumor growth of each treatment group and control group was recorded on different days of the experiment, as shown in Table 20, and the corresponding growth curves of the tumor volumes of mice in each group are shown in FIG. 13 .
  • the curative effect was evaluated according to the relative tumor proliferation rate and the relative tumor inhibition rate, and the drug efficacy analysis of each group is shown in Table 21.
  • the results of the mouse body weight changes are shown in Table 22.
  • the change curve is shown in Figure 14.
  • Table 20 Changes in tumor volume of mice in each group with treatment time in the subcutaneous model of human pancreatic cancer HPAF-II (mm 3 )
  • Table 21 Drug efficacy analysis table of each group in human pancreatic cancer HPAF-II subcutaneous model
  • the average tumor volume of the mice in the vehicle control group was 2212.64 mm 3 on the 31st day (Day 31) after the start of administration.
  • the average tumor volume of the test drug Ifosfamide in the 60mg/kg dose treatment group (group 2) on Day 31 was 2678.00mm 3 , and the relative tumor inhibition rate TGI (%) was -14.65%, which was statistically insignificant compared with the control group (p>0.05).
  • the test drug AST was in the 4mg/kg (QD ⁇ 5, 2 days off, 2 weeks off, QD ⁇ 5) and 8mg/kg (QW ⁇ 3) dose treatment groups (groups 3 and 4), and AST-3424 In the 1mg/kg (QD ⁇ 5, 2 days off, 2weeks off, QD ⁇ 5) dose group (group 5), the average tumor volumes on Day 31 were 457.66, 170.65 and 685.85mm 3 , compared with the control group, the statistically There was a significant difference (p ⁇ 0.05), and the relative tumor inhibition rates TGI (%) were 79.55%, 92.64% and 69.46%, respectively.
  • AST-3424 and AST in the model with KRAS G12D pathogenic mutation AST at 8mg/kg (QW ⁇ 3), 4mg/kg (QD ⁇ 5, 2 days off, 2 weeks off, QD ⁇ 5)
  • AST-3424 has a significant anti-tumor effect on the human pancreatic cancer HPAF-II subcutaneous model
  • the mice in each test drug treatment group did not lose weight during the treatment, and the mice were well tolerated.
  • the lung cancer LU5161 subcutaneous model is a PDX model with a KRAS G12D pathogenic mutation.
  • mice Balb/nude female mice were inoculated subcutaneously
  • the tumor mass of lung cancer LU5161 was used to establish the subcutaneous transplantation tumor model of human lung cancer.
  • the test is divided into the test drug Ifosfamide 60mg/kg single drug group (Group 2), administered once a day for 5 consecutive days, resting for 2 days, and then administered once a day for 5 consecutive days; AST 4mg/kg monotherapy Drug group (Group 3) and AST 8mg/kg single drug group (Group 4), both administered once a week for a total of 3 weeks; AST 4mg/kg single drug group (Group 5) and AST-34241mg/kg
  • the single-drug group (Group 6) was administered once a day for 5 consecutive days, rested for 2 days, rested for 2 weeks, and then administered once a day for 5 consecutive days, as well as glucose injection (pH7.
  • Vehicle control group (Group 1), administered once a day for 5 consecutive days, rested for 2 days, rested for another 2 weeks, and then administered once a day for 5 consecutive days. There were 6 groups in this study, 6 mice in each group.
  • the test drug Ifosfamide was administered intraperitoneally, and the vehicle control group, AST, and AST-3424 were all administered by tail vein injection. See Table 23 for the route of administration, dosage and regimen of the experimental design.
  • Table 23 Administration route, dose and regimen in subcutaneous model of lung cancer LU5161
  • the tumor growth of each treatment group and control group was recorded on different days of the experiment, as shown in Table 24, and the corresponding growth curves of the tumor volumes of the mice in each group are shown in FIG. 15 .
  • the curative effect was evaluated according to the relative tumor proliferation rate and the relative tumor inhibition rate, and the efficacy analysis of each group is shown in Table 25.
  • Table 24 Changes in tumor volume of mice in each group with treatment time in the subcutaneous model of lung cancer LU5161 (mm 3 )
  • Table 25 Drug efficacy analysis table of each group in the subcutaneous model of lung cancer LU5161
  • mice in the vehicle control group were 2238.97 mm 3 on the 29th day (Day 28) after the start of administration.
  • the average tumor volume of the test drug Ifosfamide in the 60mg/kg dose treatment group (Group 2) on Day 28 was 1636.39mm 3 , and the relative tumor inhibition rate TGI (%) was 27.39%. There was no statistically significant difference compared with the control group ( p>0.05).
  • AST-3424 and AST in the model with KRAS G12D pathogenic mutation show that AST-3424 and AST in the model with KRAS G12D pathogenic mutation, AST 4mg/kg (QW ⁇ 3), 8mg/kg (QW ⁇ 3), 4mg/kg (QD ⁇ 5, 2 days off, 2 weeks off, QD ⁇ 5) dose treatment groups (Group 3, Group 4 and Group 5), and AST-3424 at 1 mg/kg (QD ⁇ 5, 2 days off, 2 weeks off, QD ⁇ 5) dose Group (Group 6) under the test dosage and dosing frequency of this study, to The subcutaneous model of lung cancer LU5161 has significant anti-tumor effect. Ifosfamide administration group did not produce anti-tumor effect. The mice in each test drug treatment group tolerated well during the treatment period.
  • test substance AST and Ifosfamide monotherapy in Antitumor effect and safety evaluation of intestinal cancer CR3820 subcutaneous model
  • the colon cancer CR3820 subcutaneous model is a PDX model with a KRAS G12D pathogenic mutation.
  • NOD.SCID female mice were inoculated subcutaneously Intestinal cancer CR3820 tumor mass was used to establish a subcutaneous transplanted tumor model of human intestinal cancer.
  • the test was divided into test drug Ifosfamide, 60mg/kg monotherapy group (QD ⁇ 5/week ⁇ 2 weeks, Group 2), intraperitoneal administration, once a day, for 5 consecutive days, rest for 2 days, and then give daily AST 8 mg/kg single drug group (QW ⁇ 3, Group 3), administered via tail vein once a week for a total of 3 weeks; AST 4 mg/kg single drug Group (QD ⁇ 5, 2 days off, 2 weeks off, QD ⁇ 5, Group 4) and the vehicle control group glucose injection (pH7.7-8.0, Group 1), both were administered through the tail vein, and the administration cycle was It was administered once a day for 5 consecutive days, rested for 2 days, rested for 2 weeks, and then administered once a day for 5 consecutive days; the experiment consisted of 4 groups, 6 mice in each group. See Table 27 for the
  • Table 27 Administration route, dose and regimen in subcutaneous model of intestinal cancer CR3820
  • the tumor growth of each treatment group and control group was recorded on different days of the experiment, as shown in Table 28, and the growth curves of the tumor volumes of mice in each group are shown in FIG. 17 .
  • the curative effect was evaluated according to the relative tumor proliferation rate and the relative tumor inhibition rate, and the drug efficacy analysis of each group is shown in Table 29.
  • Record the body weight changes of the treatment group and the control group after administration, and study The safety of each group in the colon cancer CR3820 subcutaneous xenograft model, and the results of mouse body weight changes are shown in Table 30, and the curves of body weight changes over time for each treatment group are shown in Figure 18 .
  • Table 28 Changes in tumor volume of mice in each group with treatment time in the subcutaneous model of colon cancer CR3820 (mm 3 )
  • Table 29 Drug efficacy analysis table of each group in the colon cancer CR3820 subcutaneous model
  • mice in the vehicle control group were 1792.37mm 3 on the 25th day (Day 24) after the start of administration.
  • the average tumor volume of the test drug Ifosfamide in the 60mg/kg dose treatment group (QD ⁇ 5/week ⁇ 2 weeks, Group 2) on Day 24 was 1199.09mm3, and the relative tumor inhibition rate TGI (%) was 37.73%, compared with the control There was no statistically significant difference between groups (p>0.05).
  • test drug AST was dosed at 8mg/kg (QW ⁇ 3, Group 3), 4mg/kg (QD ⁇ 5, 2 days off, 2 weeks off, QD ⁇ 5, Group 4).
  • the tumor volumes were 110.59 mm 3 and 146.58 mm 3 , and the relative tumor inhibition rates TGI (%) were 94.08% and 92.44%, respectively, which were statistically significantly different from the control group (p ⁇ 0.05).
  • the test drugs Ifosfamide and AST were well tolerated at the doses tested in this study.
  • the PA2637 subcutaneous model of pancreatic cancer is a PDX model with a KRAS G12D pathogenic mutation.
  • NOD.SCID female mice were inoculated subcutaneously Pancreatic cancer PA2637 tumor mass was used to establish a subcutaneous transplanted tumor model of human pancreatic cancer.
  • the test was divided into test drug Ifosfamide, 60mg/kg monotherapy group (QD ⁇ 5/week ⁇ 2 weeks, Group 2), intraperitoneal administration, once a day, for 5 consecutive days, rest for 2 days, and then give daily The drug was administered once for 5 consecutive days; AST 8mg/kg single drug group (QW ⁇ 3, Group 3) was administered via tail vein once a week for a total of 3 weeks; AST 4mg/kg single drug group (QD ⁇ 5, 2 days off, 2 weeks off, QD ⁇ 5, Group 4), AST-3424 1mg/kg single drug group (QD ⁇ 5, 2 days off, 2 weeks off, QD ⁇ 5, Group 5) As well as the vehicle control group glucose injection (pH7.7-8.0, Group 1), both were administered through the tail vein, and the administration cycle was administered once a day for
  • Table 31 Administration route, dosage and regimen in the subcutaneous model of pancreatic cancer PA2637
  • the tumor growth of each treatment group and control group was recorded on different days of the experiment, as shown in Table 32, and the growth curves of the tumor volumes of mice in each group are shown in FIG. 19 .
  • the curative effect was evaluated according to the relative tumor proliferation rate and the relative tumor inhibition rate, and the drug efficacy analysis of each group is shown in Table 33.
  • Table 32 Changes of tumor volume of mice in each group with treatment time in PA2637 subcutaneous model of pancreatic cancer (mm 3 )
  • Table 33 Drug efficacy analysis table of each group in the subcutaneous model of pancreatic cancer PA2637
  • mice in the vehicle control group were 977.46 mm 3 on day 36 (Day 35) after the start of administration.
  • the test drug Ifosfamide in the 60mg/kg dose treatment group (Group 2) had an average tumor volume of 938.33mm3 on Day 35, and the relative tumor inhibition rate TGI (%) was 2.74%. There was no statistically significant difference compared with the control group (p >0.05).
  • the average tumor volume of the dose treatment group on Day 35 was 123.47mm 3 , 141.48mm 3 and 186.08mm 3 , and the relative tumor inhibition rate TGI (%) They were 87.28%, 85.46% and 80.78%, respectively, which were statistically significantly different from the control group (p ⁇ 0.001).
  • the lung cancer LU11873 subcutaneous model is a PDX model with a KRAS G12C pathogenic mutation.
  • NOD.SCID female mice were inoculated subcutaneously
  • the tumor mass of lung cancer LU11873 was used to establish a subcutaneous transplanted tumor model of human lung cancer.
  • the test is divided into the test drug Ifosfamide 60mg/kg single drug group (Group 2), administered once a day for 5 consecutive days, rested for 2 days, and then administered once a day for 5 consecutive days; AST 4mg /kg single drug group (Group 5), administered once a day for 5 consecutive days, rested for 2 days, rested for 2 weeks, and then administered once a day for 5 consecutive days; and glucose injection ( pH7.7-8.0) vehicle control group (Group 1), administered once a day for 5 consecutive days, rested for 2 days, rested for 2 weeks, and then administered once a day for 5 consecutive days; A total of 3 groups of 6 mice were studied.
  • the test drug Ifosfamide was administered intraperitoneally.
  • the vehicle control group and the AST groups were administered by tail vein injection. See Table 35 for the route of
  • Table 35 Administration route, dosage and regimen in subcutaneous model of lung cancer LU11873
  • Table 36 Changes in tumor volume of mice in each group with treatment time in the subcutaneous model of lung cancer LU11873 (mm 3 )
  • Table 37 Drug efficacy analysis table of each group in the subcutaneous model of lung cancer LU11873
  • the average tumor volume of the mice in the vehicle control group was 1677.89 mm 3 on the 31st day (Day 31) after the start of administration.
  • the average tumor volume on Day 31 of the test drug Ifosfamide in the 60mg/kg dose treatment group (Group 2) was 1866.37mm 3 , and the relative tumor inhibition rate TGI (%) was -10.08%, which was not statistically significant compared with the control group Difference (p>0.05).
  • the average tumor volume of the test drug AST at 4mg/kg (QD ⁇ 5, 2 days off, 2 weeks off, QD ⁇ 5) in the treatment group (Group 5) was 406.40mm 3 on Day 31, which was statistically higher than that in the control group. There was a significant difference (p ⁇ 0.05), and the relative tumor inhibition rate TGI (%) was 75.16%.
  • Example 3 the tumor inhibitory effect of AST in the KRAS pathogenic mutation model lung cancer LU11693 with G12C amino acid mutation was not obvious, and the TGI% was 54.64% at a dose of 10 mg/kg; while in this example Among them, AST had a significant anti-tumor effect in the lung cancer LU11873 model with KRAS G12C pathogenic mutation, and the TGI% was 75.16% at a dose of 4mg/kg.
  • LU11693 was derived from a 58-year-old female patient who clinically showed cachexia and mild ulcers;
  • LU11873 was derived from a 51-year-old male patient who clinically showed mild weight loss and mild ulceration.
  • test substance AST and Ifosfamide monotherapy in Antitumor effect and safety evaluation of PA1383 subcutaneous model of pancreatic cancer
  • the PA1383 subcutaneous model of pancreatic cancer is a PDX model with a KRAS G12C pathogenic mutation.
  • mice Balb/nude female mice were inoculated subcutaneously Pancreatic cancer PA1383 tumor mass was used to establish a subcutaneous transplanted tumor model of human pancreatic cancer.
  • the test is divided into the test drug Ifosfamide 60mg/kg single drug group (Group 2), administered once a day for 5 consecutive days, resting for 2 days, and then administered once a day for 5 consecutive days; AST 8mg/kg monotherapy
  • the drug group (Group 4) was administered once a week for a total of 3 weeks;
  • the AST 4mg/kg single drug group (Group 5) was administered once a day for 5 consecutive days, rested for 2 days, and then rested for 2 days.
  • Table 39 Administration route, dose and regimen in the subcutaneous model of pancreatic cancer PA1383
  • the tumor growth of each treatment group and control group was recorded on different days of the experiment, as shown in Table 40, and the growth curves of the tumor volumes of mice in each group are shown in FIG. 23 .
  • the curative effect was evaluated according to the relative tumor proliferation rate and the relative tumor inhibition rate, and the drug efficacy analysis of each group is shown in Table 41.
  • Table 40 Changes of tumor volume of mice in each group with treatment time in PA1383 subcutaneous model of pancreatic cancer (mm 3 )
  • Table 41 Drug efficacy analysis table of each group in the subcutaneous model of pancreatic cancer PA1383
  • mice in the vehicle control group were 1536.48 mm 3 on the 31st day (Day 31) after the start of administration.
  • the average tumor volume on Day 31 of the test drug Ifosfamide in the 60mg/kg treatment group (Group 2) was 1202.01mm 3 , and the relative tumor inhibition rate TGI (%) was 21.84%. Compared with the control group, there was no statistically significant difference (p>0.05).
  • the average tumor volume of the test drug AST at 8 mg/kg (QW ⁇ 3) and 4 mg/kg (QD ⁇ 5, 2 days off, 2 weeks off, QD ⁇ 5) in the treatment groups (Group 4 and Group 5) on Day 31 were respectively They were 18.57mm 3 and 39.94mm 3 , which were statistically significantly different from the control group (p ⁇ 0.05), and the relative tumor inhibition rates TGI (%) were 98.72% and 97.46%, respectively, and each had 2 small The tumors of the mice were completely cleared, with a clearance rate of 33.3%.
  • the AKR1C3LOG2 (FPKM) of GA6201 was 6.78, LU11693 was 11.14, PA1222 was 7.39, HPAF-II was 8.31, LU5161 was 11.56, CR3820 was 8.34, PA2637 was 9.12, LU11873 was 10.26, and PA1383 was 9.57, see Table 43.
  • the AKR1C3 protein content of these three tissues was determined (commercial IHC reagents were used, the primary antibody was rabbit antibody Rabbit IgG mAb from Abcam Company, and the secondary antibody was optimized polymer from Leica Company Detection system Bond Polymer Refine Detection, staining conditions: antigen retrieval 100°C, pH 9.0 EDTA buffer 20min, dilution ratio: 1:800), and H-SCORE scoring of the staining results: immunohistochemical staining intensity will be divided into 0 (negative), 1+ (weak staining), 2+ (medium staining), 3+ (strong staining), manually set the thresholds of weak staining, medium staining, and strong staining on the scoring instrument, and then use image processing software to perform staining The sample photos are color-identified, and the staining photos of all samples are scored according to a unified standard, and the staining situation corresponding
  • H-Score was calculated as the IHC result score of each sample by the following formula. The H-score will be between 0 and 300, and the higher the score, the higher the expression level of the target (AKR1C3 enzyme protein) corresponding to the antibody in the sample. Calculated as follows:
  • H-Score (%at 0) ⁇ 0+(%at 1) ⁇ 1+(%at 2) ⁇ 2+(%at 3) ⁇ 3
  • Table 44 IHC results and H-SCORE scores of GA6201, LU11693, PA1222 models and control groups
  • AST-3424 and AST have a positive effect on cancers with high expression of AKR1C3 and KRAS pathogenic mutations with G12D amino acid mutations.
  • AST may have a significant therapeutic effect on cancers with high expression of AKR1C3 and KRAS pathogenic mutations with G12C amino acid mutations.
  • AKR1C3 in some tumors may be associated with KARS (pathogenic) mutation subtypes, that is, the high expression or overexpression of AKR1C3 in some tumors is often associated with certain subtypes of KARS (pathogenic) mutations co-existence, and this phenomenon would lead to tumor models with these characteristics being more sensitive to AST-3424 or AST.
  • PCT/NZ2019/050030 publication number WO2019190331A1 (corresponding to Chinese application number 2019800234236, publication number CN111918864A);
  • AKR1C3-activated DNA alkylating agent prodrug is useful for the treatment of cancer and tumor patients with KRAS mutation, especially KRAS-G12D subtype mutation. patients had a significant therapeutic effect.

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WO2024251193A1 (zh) 2023-06-06 2024-12-12 深圳艾欣达伟医药科技有限公司 通过kras突变来关联akr1c3酶表达水平及医药用途
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023237080A1 (zh) 2022-06-10 2023-12-14 深圳艾欣达伟医药科技有限公司 Akr1c3酶激活前药治疗癌症患者的方法
WO2024251193A1 (zh) 2023-06-06 2024-12-12 深圳艾欣达伟医药科技有限公司 通过kras突变来关联akr1c3酶表达水平及医药用途
WO2025082484A1 (zh) 2023-10-18 2025-04-24 深圳艾欣达伟医药科技有限公司 治疗p53基因突变阴性、kras基因突变阳性、brca突变阳性患者

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CN115869325A (zh) 2023-03-31
WO2023046060A8 (zh) 2023-11-09
JP2024535913A (ja) 2024-10-02
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