A DBAIT MOLECULE IN COMBINATION WITH KRAS INHIBITOR FOR THE TREATMENT OF CANCER
The present invention relates to the combination of a Dbait molecule with a KRAS inhibitor for treating cancer.
1 - 16 . (canceled)
17 . A pharmaceutical composition comprising a Dbait molecule and a protein KRAS inhibitor, wherein the Dbait molecule has one of the following formulae:
wherein N is a deoxynucleotide, n is an integer from 15 to 195, the underlined N refers to a nucleotide having or not a modified phosphodiester backbone, L′ is a linker, C is the molecule facilitating endocytosis selected from a lipophilic molecule or a ligand which targets cell receptor enabling receptor mediated endocytosis, L is a linker, m and p, independently, are an integer being 0 or 1.
18 . The pharmaceutical composition according to claim 17 , wherein the Dbait molecule has the following formula:
19 . The pharmaceutical composition according to claim 17 , wherein the KRAS inhibitor is a direct KRAS inhibitor selected from the group consisting of specific covalent KRAS inhibitors and multivalent small-molecule pan KRAS inhibitors.
20 . The pharmaceutical composition according to claim 19 , wherein the KRAS inhibitor is selected from the group consisting of AMG-510/sotorasib (Amgen/Carmot Therapeutics), MRTX-849/Adagrasib (Mirati Therapeutics), ARS-3248/JNJ-74699157 (Johnson & Johnson/Wellspring Biosciences), Compound B (Sanofi/X-Chem Pharmaceuticals), LY3499446 (Eli Lilly), ARS-853, ARS-1620, BI-2852, BI-1701963 (Boehringer Ingelheim), mRNA-5671 (Moderna Therapeutics), G12D inhibitor (Mirati), RAS(On)inhibitors (Revolution medicines), and BBP-454 (BridgeBio Pharma).
21 . The pharmaceutical composition according to claim 19 , wherein the KRAS inhibitor is a KRASG12C inhibitor directly targeting and binding mutant KRASG12C protein.
22 . The pharmaceutical composition according to claim 17 , wherein the KRAS inhibitor leaves wild-type KRAS protein untouched.
23 . A combination comprising a Dbait molecule and a protein KRAS inhibitor, wherein the Dbait molecule has one of the following formulae:
wherein N is a deoxynucleotide, n is an integer from 15 to 195, the underlined N refers to a nucleotide having or not a modified phosphodiester backbone, L′ is a linker, C is the molecule facilitating endocytosis selected from a lipophilic molecule or a ligand which targets cell receptor enabling receptor mediated endocytosis, L is a linker, m and p, independently, are an integer being 0 or 1.
24 . The combination according to claim 23 , wherein the Dbait molecule has the following formula:
25 . The combination according to claim 23 , wherein the KRAS inhibitor is a direct KRAS inhibitor selected from the group consisting of specific covalent KRAS inhibitors and multivalent small-molecule pan KRAS inhibitors.
26 . The combination according to claim 25 , wherein the KRAS inhibitor is selected from the group consisting of AMG-510/sotorasib (Amgen/Carmot Therapeutics), MRTX-849/Adagrasib (Mirati Therapeutics), ARS-3248/JNJ-74699157 (Johnson & Johnson/Wellspring Biosciences), Compound B (Sanofi/X-Chem Pharmaceuticals), LY3499446 (Eli Lilly), ARS-853, ARS-1620, BI-2852, BI-1701963 (Boehringer Ingelheim), mRNA-5671 (Moderna Therapeutics), G12D inhibitor (Mirati), RAS(On)inhibitors (Revolution medicines), and BBP-454 (BridgeBio Pharma).
27 . The combination according to claim 25 , wherein the KRAS inhibitor is a KRASG12C inhibitor directly targeting and binding mutant KRASG12C protein.
28 . The combination according to claim 25 , wherein the KRAS inhibitor leaves wild-type KRAS protein untouched.
29 . A method of treating cancer comprising administering a pharmaceutical composition according to claim 23 to a subject in need of treatment.
30 . The method according to claim 29 , wherein the cancer is a cancer driven by a KRAS mutation selected from the group consisting of KRASG12C, KRASG12V, KRASG12S, KRASG12D, KRASG13C, KRASG13D, KRASG12C, and KRASG12D.
31 . The method according to claim 29 , wherein the cancer is selected from the group consisting of a cancer of head and neck, pancreas, stomach, colon, colorectum, small intestine, biliary tract, kidney, ovary, prostate, thyroid, esophagus, breast, bladder, lung, liver, uterine corpus, endometrium, cervix, urinary tract, peritoneal cancers, multiple myeloma, sarcoma, skin cancer, melanoma, uveal melanoma, and hematopoietic cancers.
32 . A method of treating cancer comprising administering a therapeutically effective amount of a combination according to claim 23 to a subject in need of treatment.
33 . The method according to claim 32 , wherein the cancer is a cancer driven by a KRAS mutation selected from the group consisting of KRASG12C, KRASG12V, KRASG12S, KRASG12D, KRASG13C, KRASG13D, KRASG12C, and KRASG12D.
34 . The method according to claim 32 , wherein the cancer is selected from the group consisting of a cancer of head and neck, pancreas, stomach, colon, colorectum, small intestine, biliary tract, kidney, ovary, prostate, thyroid, esophagus, breast, bladder, lung, liver, uterine corpus, endometrium, cervix, urinary tract, peritoneal cancers, multiple myeloma, sarcoma, skin cancer, melanoma, uveal melanoma, and hematopoietic cancers.
35 . A method of delaying the development of a cancer resistant to a KRAS inhibitor in a patient comprising administering a composition according to claim 17 to a patient in need of treatment.
36 . A method of delaying the development of a cancer resistant to a KRAS inhibitor in a patient comprising administering a combination according to claim 23 to a patient in need of treatment.
37 . A method of treating cancer persister cells is a subject having cancer comprising administering a composition according to claim 17 to said subject.
38 . A method of treating cancer persister cells is a subject having cancer comprising administering a combination according to claim 23 to said subject.