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US-20260125386-A1 - COMPOSITIONS AND METHODS FOR INHIBITION OF KRAS

US20260125386A1US 20260125386 A1US20260125386 A1US 20260125386A1US-20260125386-A1

Abstract

Provided herein are compounds, or salts, esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers thereof, as well as pharmaceutical compositions comprising the same. Also provided herein are methods of using the same in modulating (e.g., inhibiting) KRAS (e.g., KRAS having a Q61H, G12D, G12V, G12C, G12S, G12A, G12R, or G13D mutation or wild-type KRAS) and treating diseases or disorders such as cancers in subjects in need thereof.

Inventors

  • Zuhui Zhang
  • David Michael Turner
  • Dhirendra Kumar Simanshu
  • Albert Hay Wah Chan
  • Christopher John Brassard
  • Tao LIAO
  • Bin Wang
  • Eli Wallace
  • Rui Xu
  • Paul WEHN
  • Yue Yang
  • Felice LIGHTSTONE
  • Jun Pei
  • Anna Elzbieta Maciag

Assignees

  • THERAS, INC.
  • LEIDOS BIOMEDICAL RESEARCH, INC.
  • LAWRENCE LIVERMORE NATIONAL SECURITY, LLC

Dates

Publication Date
20260507
Application Date
20260105

Claims (20)

  1. 1 - 349 . (canceled)
  2. 350 . A compound having the structure: or a pharmaceutically acceptable salt thereof.
  3. 351 . A compound having the structure: or an atropisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the atropisomer thereof.
  4. 352 . A compound having the structure: or a pharmaceutically acceptable salt thereof.
  5. 353 . The compound of claim 350 , wherein the compound is
  6. 354 . The compound of claim 351 , wherein the compound is or an atropisomer thereof.
  7. 355 . The compound of claim 352 , wherein the compound is
  8. 356 . A pharmaceutical composition comprising a compound of claim 350 , or a pharmaceutically acceptable salt thereof.
  9. 357 . The pharmaceutical composition of claim 356 , wherein the compound is
  10. 358 . A pharmaceutical composition comprising a compound of claim 351 , or an atropisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the atropisomer thereof.
  11. 359 . The pharmaceutical composition of claim 358 , wherein the compound is or an atropisomer thereof.
  12. 360 . A pharmaceutical composition comprising a compound of claim 352 , or a pharmaceutically acceptable salt thereof.
  13. 361 . The pharmaceutical composition of claim 360 , wherein the compound is
  14. 362 . A compound selected from: or a salt thereof.
  15. 363 . The compound of claim 362 , wherein the compound is or a salt thereof.
  16. 364 . The compound of claim 363 , wherein the compound is
  17. 365 . The compound of claim 362 , wherein the compound is or a salt thereof.
  18. 366 . The compound of claim 365 , wherein the compound is
  19. 367 . The compound of claim 362 , wherein the compound is or a salt thereof.
  20. 368 . The compound of claim 367 , wherein the compound is

Description

RELATED APPLICATIONS This application claims priority to and benefit of U.S. Application No. 63/395,699, filed Aug. 5, 2022, U.S. Application No. 63/386,285, filed Dec. 6, 2022, and U.S. Application No. 63/496,873, filed Apr. 18, 2023, the entire contents of each of which are hereby incorporated by reference. STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT This invention was made with government support under (1) Contract No.: 75N91019D00024 awarded by the National Institutes of Health and (2) Contract No. DE-AC52-07NA27344 awarded by the United States Department of Energy. The government has certain rights in the invention. BACKGROUND RAS protein functions as a molecular switch, cycling between inactive (“GDP-bound”) and active (“GTP-bound”) states. RAS signaling occurs through engagement with effector proteins that adapt the signaling cascades regulating tumor cell survival and proliferation. Aberrant activation of RAS by oncogenic mutations results in increased GTP-bound KRAS and constitutive downstream signaling. RAS is the most frequently mutated oncogene. Activating mutations in KRAS occur in over 90% of pancreatic tumors. Mutated KRAS is also observed at high frequency in other common tumors, including colorectal cancer (˜44%) and non-small cell lung cancer (NSCLC; ˜20-30%). Cancer-associated mutations in KRAS cluster in three hotspots (G12, G13, and Q61), with a majority (77%) of mutations causing single amino acid substitutions at G12. The KRAS missense mutation G12D is the most predominant variant in human malignancies (35%), followed by G12V (29%). Besides G12, the hotspots G13 and Q61 show mutation rates of 10% and 6% respectively. The development of small molecule KRAS inhibitors has proven to be a challenge. Recent clinical development of covalent KRAS G12C inhibitors indicates potential of targeting the KRAS oncogenic protein directly. Results from clinical trials with the two covalent inhibitors, AMG510 (sotorasib) and MRTX849 (adagrasib), have been promising. These inhibitors demonstrated clinical activity primarily in NSCLC, where the KRAS G12C mutation frequency is highest. Unfortunately, they appeared less effective in KRAS G12C colorectal cancers. Both compounds only target the inactive (GDP-bound) form of KRAS G12C, and a lack of activity against active (GTP-bound) KRAS G12C may contribute to development of drug resistance. Moreover, these covalent inhibitors are limited to the specific G12C mutant that accounts for approximately 13% of all KRAS-driven cancers, leaving a large population of non-G12C KRAS cancers still undruggable. Therefore, KRAS therapeutics that target additional KRAS alterations or combinations thereof are an unmet clinical need. Pan-KRAS inhibitors hold promise for impact across the majority of KRAS mutant alleles, including the most prevalent G12D and G12V, or KRAS wildtype-amplified cancers. KRAS is essential for mouse development, whereas NRAS and HRAS are dispensable. This requirement for KRAS creates toxicity concerns when targeting the wild-type KRAS protein. However, when KRAS is replaced with HRAS, mice are viable, which reduces toxicity concerns and suggests that in contrast to the pan-RAS inhibitors that could pose toxicity issues, KRAS isoform-specific inhibitors should be tolerated. If so, additional advantages of pan-KRAS inhibitors could come from targeting cancers with acquired resistance to KRAS G12C inhibitors. Recent reports provide insights into mechanisms of resistance to the KRAS G12C inhibitors in the clinic, suggesting restoration of RAS/MAPK as a driver of the resistance. Acquisition of a diverse set of mutations in response to KRAS G12C inhibitors in addition to activation of the KRAS wildtype allele through upstream RTK signaling has been shown. It is possible that direct pan-KRAS agents may suppress these events. Accordingly, there remains a need for allele-specific and pan-KRAS inhibitors that could be used to treat KRAS-driven cancers regardless of mutation status. SUMMARY The present disclosure provides compounds, as well as compositions and kits comprising the same, and methods of using the same in the treatment of diseases and disorders such as cancers. The present disclosure provides compounds that may be capable of inhibiting one or more mutant forms of KRAS, such as KRAS having a G12D, G12V, G12C, G12S, G12A, G12R, Q61H, or G13D mutation, or wild-type KRAS. Such compounds may be considered pan-KRAS inhibitors. In some embodiments, the compounds provided herein may be capable of targeting both active GTP-bound protein and inactive GDP-bound protein, which inhibitors may provide therapeutic advantages over compounds capable of targeting only the inactive GDP-bound protein. In some embodiments, compounds provided herein have inhibitory activity against a KRAS protein comprising a glycine to aspartic acid, valine, cysteine, serine, alanine, or arginine mutation at codon 12 (i.e., a G12D, G1