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CN-121985942-A - Compounds that re-activate mutant p53

CN121985942ACN 121985942 ACN121985942 ACN 121985942ACN-121985942-A

Abstract

The present disclosure relates to compounds that restore p53 activity and methods of using the compounds to treat various disorders associated with loss of p53 activity, such as cancers, e.g., sarcomas, epithelial cancers, head and neck cancers, hematological cancers, solid tumors, breast cancers, cervical cancers, gastrointestinal cancers, colorectal cancers, brain cancers, skin cancers, prostate cancers, ovarian cancers, thyroid cancers, testicular cancers, pancreatic cancers, liver cancers, endometrial cancers, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative diseases, myelodysplastic syndrome, myeloproliferative tumors, non-small cell lung cancers, kidney cancers, lung cancers, colon cancers, cervical cancers, and plasma cell tumors (myeloma). This abstract is intended as a scanning tool for searching purposes in particular areas and is not intended to limit the present invention.

Inventors

  • John Karaniklas
  • Sven Miller
  • Karen Carl

Assignees

  • 癌症研究所(D/B/A福克斯切斯癌症中心研究所)

Dates

Publication Date
20260505
Application Date
20240522
Priority Date
20230523

Claims (20)

  1. 1. A pharmaceutical composition comprising an effective amount of a compound having a structure represented by the formula: , Wherein R 1 is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, - (C1-C4 alkyl) O (C1-C4 alkyl), -CH 2 Ar 1 , and-Ar 1 ; Wherein Ar 1 when present is a 6-membered aryl group substituted with 0,1, 2, or 3 groups independently selected from halogen, -CN, -NH 2 、-OH、-NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4) (C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO 2 H, and-CO 2 (C1-C4 alkyl); Wherein R 2 is selected from hydrogen and C1-C4 alkyl, and Wherein R 3a 、R 3b 、R 3c 、R 3d and R 3e are each independently selected from the group consisting of hydrogen, halogen, -CN, -NH 2 、-OH、-NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4) (C1-C4) dialkylamino and C1-C4 aminoalkyl, Or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  2. 2. The pharmaceutical composition of claim 1, wherein R 1 is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, and- (C1-C4 alkyl) O (C1-C4 alkyl).
  3. 3. The pharmaceutical composition of claim 1, wherein R 1 is selected from-CH 2 Ar 1 and-Ar 1 .
  4. 4. The pharmaceutical composition of claim 3, wherein Ar 1 is a 6-membered aryl, said 6-membered aryl being monosubstituted with a group selected from halogen, -CN, -NH 2 、-OH、-NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO 2 H and-CO 2 (C1-C4 alkyl).
  5. 5. The pharmaceutical composition of claim 3, wherein Ar 1 is a 6-membered aryl substituted with 1or2 groups selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, and-CO 2 (C1-C4 alkyl).
  6. 6. The pharmaceutical composition of claim 3, wherein Ar 1 is a 6-membered aryl substituted with 1 or 2 groups selected from-F, -Cl, methyl, ethyl, methoxy, ethoxy, -CO 2 CH 3 , and-CO 2 CH 2 CH 3 .
  7. 7. The pharmaceutical composition of claim 3, wherein Ar 1 is unsubstituted 6 membered aryl.
  8. 8. The pharmaceutical composition of any one of claims 1 to 7, wherein R 2 is hydrogen.
  9. 9. The pharmaceutical composition of any one of claims 1 to 7, wherein R 2 is C1-C4 alkyl.
  10. 10. The pharmaceutical composition of any one of claims 1 to 9, wherein R 3a 、R 3b 、R 3c 、R 3d and R 3e are each independently selected from hydrogen, halogen, C1-C4 alkyl, and C1-C4 alkoxy.
  11. 11. The pharmaceutical composition of any one of claims 1 to 9, wherein R 3a 、R 3b 、R 3c 、R 3d and R 3e are each independently selected from hydrogen, -F, -Cl, methyl, ethyl, methoxy, and ethoxy.
  12. 12. The pharmaceutical composition of any one of claims 1 to 9, wherein R 3a 、R 3b 、R 3c 、R 3d and R 3e are each hydrogen.
  13. 13. The pharmaceutical composition of claim 1, wherein the compound has a structure represented by the formula: , wherein n is selected from the group consisting of 0 and 1, Or a pharmaceutically acceptable salt thereof.
  14. 14. The pharmaceutical composition of claim 13, wherein the compound has a structure represented by the formula: , Wherein R 10a 、R 10b 、R 10c 、R 10d , and R 10e are each independently selected from the group consisting of hydrogen, halogen, -CN, -NH 2 、-OH、-NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4) (C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO 2 H, and-CO 2 (C1-C4 alkyl), Or a pharmaceutically acceptable salt thereof.
  15. 15. The pharmaceutical composition of claim 14, wherein at least two of R 10a 、R 10b 、R 10c 、R 10d and R 10e are hydrogen.
  16. 16. The pharmaceutical composition of claim 14, wherein at least three of R 10a 、R 10b 、R 10c 、R 10d and R 10e are hydrogen.
  17. 17. The pharmaceutical composition of claim 14, wherein the compound has a structure represented by the formula: , or a pharmaceutically acceptable salt thereof.
  18. 18. The pharmaceutical composition of claim 1, wherein the compound is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.
  19. 19. A pharmaceutical composition comprising an effective amount of a compound selected from the group consisting of: Or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  20. 20. A method of restoring p53 activity in a cell, the method comprising contacting the cell with an effective amount of a compound having a structure represented by the formula: , Wherein R 1 is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, - (C1-C4 alkyl) O (C1-C4 alkyl), -CH 2 Ar 1 , and-Ar 1 ; Wherein Ar 1 when present is a 6-membered aryl group substituted with 0,1, 2, or 3 groups independently selected from halogen, -CN, -NH 2 、-OH、-NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4) (C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO 2 H, and-CO 2 (C1-C4 alkyl); Wherein R 2 is selected from hydrogen and C1-C4 alkyl, and Wherein R 3a 、R 3b 、R 3c 、R 3d and R 3e are each independently selected from the group consisting of hydrogen, halogen, -CN, -NH 2 、-OH、-NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4) (C1-C4) dialkylamino and C1-C4 aminoalkyl, Or a pharmaceutically acceptable salt thereof.

Description

Compounds that re-activate mutant p53 Cross Reference to Related Applications The application claims the benefit of U.S. application Ser. No. 63/468,476, filed on 5/23 of 2023, the contents of which are hereby incorporated by reference in their entirety. Statement regarding federally sponsored research The present invention was made with government support under grant numbers 5R01GM112736 and 5T32CA009035 awarded by the National Institutes of Health (NIH). The government has certain rights in this invention. Background Somatic mutations in the TP53 gene occur in almost every adult malignancy and represent the most common genetic defect in tumor genome sequencing (Rivlin et al (2011) Genes cancer.2:466-74). In the germline, genetic Pathogenic Variations (PV) in TP53 (characteristic of clinical Li-Fraumeni syndrome (LFS)) are rare. The estimated prevalence of these PVs is about 1/3500-1/5500, associated with early life and high risk of multiple cancers (DE ANDRADE et al (2019) Hum Mutat.40:97-105; mai et al (2016) Cancer20122:3673-81; schneider et al (1993) GENEREVIEWS ((R))). In addition to increasing the risk of colorectal, leukemia and adrenocortical cancers, LFS also greatly increases the risk of breast Cancer (up to 54% by age 70), childhood and adult soft tissue sarcomas (15% -22% life-long risk) and brain tumors (6% -19% life-long risk) (Mai et al (2016) Cancer 20122:3673-81). Overall, germ line carriers of pathogenic variation in TP53 have estimated a lifetime risk (penetrance) of any cancer of up to 90% in females and up to 70% in males (Rana et al (2018) J NATL CANCER Inst. 110:863-70). The incidence of pathogenic variation in the novel germline in TP53 is estimated to be about 10% -20% (Gonzalez et al (2009) J Clin Oncol.27:1250-6; gonzalez et al (2009)J Med Genet.46:689-93) "The biological underpinnings of therapeutic resistance in pancreatic cancer"Genes Dev). In the LFS family, intensive monitoring is required to detect pre-cancerous lesions (e.g., colorectal polyps) and diagnose/prevent invasive cancers at the earliest stage, when curative treatment may be available (Villani et al (2016)Lancet Oncol17:1295-305; The National Comprehensive Cancer Network Clinical Practice Guidelines® in Oncology: Li-Fraumeni syndrome (Version 1.2015). ©2015 National Comprehensive Cancer Network, Inc. 2019). suggest that LFS individuals conduct neurological examination, whole body MRI examination (annually), and abdominal ultrasound examination (every 3-4 months) during childhood and adolescence.) adult females begin to conduct mammography and breast MRI examination annually (partial patient undergo surgical prophylaxis) during the age of 20 years (e.g., bilateral mastectomy), adult males and females begin annual skin examination and upper and lower gastrointestinal endoscopy every 2-5 years from 25 years (Frebourg et al (2020) Eur J Hum genet.28:1379-86). The TP53 variants in most LFS are missense and map almost entirely to the DNA binding "core domain" of p53 (Malkin (2011) GENES CANCER 2:475-84). In 40% -60% of cases, tumors from LFS patients also lost WT alleles (loss of heterozygosity) (Varley et al (1997) Br J Cancer76:1-14; shetzer et al (2014) CELL DEATH DIFFER 21:1419-31). Except for One particular Brazil LFS initiating mutation (Giacomazzi et al (2014) PLoS One 9:e 99893), the distribution of germ line mutations in LFS closely matches that observed in cancers with somatic TP53 mutations (Walerych et al (2012) Carcinogenic sis 33:2007-17). While some of these mutations map undesirably to residues that are in direct contact with DNA, many mutations are not (fig. 1A). Importantly, the biophysical changes in p53 structure induced by many of these PVs motivate potential interception strategies. From a thermodynamic point of view, the wild-type p53 is only marginally stable (Bullock et al (1997) Proc NATL ACAD SCI USA94:14338-42; butler and Loh (2006) Protein Sci.15:2457-65). Then, many of the most frequently occurring inactivating mutations reduce the conformational stability of the core domain, allowing the protein to in turn assume an unfolded (or misfolded) conformation (Bullock et al (2000) Oncogene 19:1245-56). This mechanism is supported by the observation that compensatory ("second site inhibitor") mutations, which stabilize p53 (Baroni et al (2004) Proc NATL ACAD SCI USA. 101:4930-5), or reduce its propensity to aggregate (Xu et al (2011) Nat Chem biol. 7:285-95), can rescue the loss of function associated with these specific inactivating mutations. Taken together, these observations strongly suggest that compounds with the ability to re-stabilize p53 can reverse the pathophysiological effects of certain LFS mutations. Investigation of a variety of cancers with somatic missense mutations in TP53 revealed three key aspects of p53 activity. First, in view of the strong tumor suppression of p53, expression of wild-type p53 was lost in >93% of these cancers (loss of heterozygosity) (Parikh et al (2014) J