IP Library › Granted Patent US 11,931,347

Granted Patent B2

US 11,931,347 · App. 15/762,897 · Granted Mar 19, 2024

Method of screening for agents for differentiating stem cells

Inventors: Cynthia Bamdad (Waltham, MA); Scott Moe (Waltham, MA)

Assignee: MINERVA BIOTECHNOLOGIES CORPORATION

A61K31/437 A61K31/4045 A61K31/444 A61P29/00 A61P35/04 C12Q1/686 C12Q1/6886 G01N33/5073 G01N33/574 C12Q2600/136 C12Q2600/158 G01N2800/7028

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 11,931,347
App. No.: 15/762,897
Granted: Mar 19, 2024
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

The present application discloses a method for identifying an agent for the treatment or prevention of cancer or metastatic cancer comprising the steps of contacting stem cell with a potential agent, and identifying an agent that induces differentiation, or inhibits stem cell pluripotency or growth of the stem cell, wherein such agent is determined to be an anti-cancer agent.

Claims (107)

1. A method of treating cancer in a subject, wherein the cancer is a MUC1 positive or MUC1* positive cancer, the method comprising administering to the subject a compound of Formula 5, Formula 6, Formula 7, or Formula 9;

wherein,

R1 is H, optionally substituted C1-C6 alkyl; or optionally substituted unsubstituted C3-C8 cycloalkyl;

R2 is hydrogen, C1-C6 alkoxy, trifluoromethyl, halogen, methylcarboxy, ethylcarboxy, optionally substituted C1-C6 alkyl, —OH, —SH, —NH 2 , —N 3 , —CN, —NO 2 , —CHO, —COOH, —CONH 2 , —C(═NH)NH 2 , or —SO 3 H;

G1 is —(CH 2 ) n —, —CH═CH—, or —C3-C7 cycloalkylene-CH 2 —;

Z2 is a bond, —NH—, —O—, —S—, —CH(CH 3 )—, —(CH 2 ) n —, —CH═CH—, —CO—, —SO—, —SO 2 —, —C(═NH)—, —CH 2 NH(CO)—, —CH 2 NH(CO)O—, —CH 2 NH(CO)NH—; —(CH 2 ) p NH(CO)—, —(CH 2 ) p NH(CO)O—, —(CH 2 ) p NH(CO)NH—, —C3-C7 cycloalkylene-NH(CO)—, —C3-C7 cycloalkylene-CH 2 NH(CO)O—, —C3-C7 cycloalkylene-NH(CO)NH—, —N(CH 2 CH 2 C 6 H 5 )—, or optionally substituted C6-C12 arylene;

R5 is H, C1-C6 alkyl, or 2-phenylethyl;

R4 is H, optionally substituted C1-C9 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C6-C12 aryl, optionally substituted C1-C9 heteroaryl with 1 to 4 ring atoms independently selected from N, S, and O, optionally substituted C7-C15 arylalkyl, optionally substituted C3-C7 cycloalkyl, —(CH 2 ) p —NH(CO)O—(C1-C6 alkyl), —CH 2 O(CH 2 ) p —NH(CO)O—(C1-C6) alkyl; —(CH 2 ) p —NHCO—(CH 2 ) n —NH(CO)O—C1-C6 alkyl), —NH(CO)O-tert-butyl, —O-tert-butyl, or -tert-butyl;

each n is indpendentl selected from 1-8; each p is independently selected from 1-9;

where “substituted” means substituted with one or more substituents independently selected from halogen, trifluoromethyl, methylcarboxy, ethylcarboxy, C1-C6 alkoxy, C1-C6 alkyl, —OH, —SH, —NH 2 , —N 3 , —CN, —NO 2 , —CHO, —COOH, —CONH 2 , —C(═NH)NH 2 , or —SO 3 H;

wherein,

R1 is H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C8 cycloalkyl;

G1 is —(CH 2 ) n —, —CH═CH—, or —C3-C7 cycloalkylene-CH 2 —;

R5 is H, C1-C6 alkyl, or 2-phenylethyl;

X is H, or C1-C3 alkyl;

each n is independently selected from 1-8; each p is independently selected from 1-9;

wherein,

R1 is H, optionally substituted C1-C6 alkyl; optionally substituted C2-C6 alkenyl; optionally substituted C1-C6 alkoxy; optionally substituted C1-C9 heteroaryl with 1 to 4 ring atoms independently selected from N, S, and O, optionally substituted C7-C15 arylalkyl, optionally substituted C2-C15 heteroarylalkyl with 1 to 4 ring atoms independently selected from N, S, and O, optionally substituted arylalkenyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted C4-C8 cycloalkylalkyl;

R2 is hydrogen, C1-C6 alkoxy, trifluoromethyl, halogen, methylcarboxy, ethylcarboxy, optionally substititued C1-C6 alkyl, —OH, —SH, —NH 2 , —N 3 , —CN, —NO 2 , —CHO, —COOH, —CONH 2 , —C(═NH)NH 2 , or —SO 3 H;

G2 is a bond, —(CH 2 ) n —, —CH═CH—, CH 2 NH(CO)—, —CH 2 NH(CO)O—, —CH 2 NH(CO)NH—; —(CH 2 ) n NH(CO)—, —(CH 2 ) n NH(CO)O—, —(CH 2 ) m NH(CO)NH—, or —C3-C7 cycloalkylene-,

Z2 is a bond, —NH—, —O—, —S—, —CH(CH 3 )—, —(CH 2 ) n —, —CH═CH—, —CO—, —SO—, —SO 2 — or —C(═NH)—, —CH 2 NH(CO)—, —CH 2 NH(CO)O—, —CH 2 NH(CO)NH—, —(CH 2 ) p NH(CO)—, —(CH 2 ) p NH(CO)O—, —(CH 2 ) p NH(CO)NH—, —C3-C7 cycloalkylene-NH(CO)—, —C3-C7 cycloalkylene-CH 2 NH(CO)O—, —C3-C7 cycloalkylene-NH(CO)NH—, or —N(CH 2 CH 2 C 6 H 5 )—;

R5 is H, C1-C6 alkyl, or 2-phenylethyl;

X is H, or C1-C3 alkyl;

each n is independenty selected from 1-8; each p is independently selected from 1-8; p=1-9;

wherein,

R1 is H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C1-C6 alkoxy, optionally substituted C6-C12 aryl, optionally substituted C1-C9 heteroaryl with 1 to 4 ring atoms independently selected from N, S, and O, optionally substituted C7-C15 arylalkyl, optionally substituted C2-C15 heteroarylalkyl with 1 to 4 ring atoms independently selected from N, S, and O, optionally substituted C7-C15 arylalkenyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted C4-C8 cycloalkylalkyl;

R5 is H, C1-C6 alkyl, or 2-phenylethyl;

X is H, or C1-C3 alkyl;

Z2 is a bond, —NH—, —O—, —S—, —CH(CH 3 )—, —(CH 2 ) n —, —CH═CH—, —CO—, —SO—, —SO 2 —, —C(═NH)—, —CH 2 NH(CO)—, —CH 2 NH(CO)O—, —CH 2 NH(CO)NH—, —(CH 2 ) n NH(CO)—, —(CH 2 ) n NH(CO)O—, —(CH 2 ) m NH(CO)NH—, —C3-C7 cycloalkylene-NH(CO)—, —C3-C7 cycloalkylene-CH 2 NH(CO)O—, —C3-C7 cycloalkylene-NH(CO)NH—, or —N(CH 2 CH 2 C 6 H 4 )—;

each p is indepedently selected from 1-5; each n is independently selected from 1-8;

2. The method according to claim 1 , wherein the cancer is an NME7 AB or NME7-X1 positive cancer.

3. The method according to claim 1 , further comprising

analyzing a cancerous sample from the subject and determining that it is MUC1* positive, NME7 AB positive or NME7-X1 positive.

4. The method according to claim 3 , wherein the analyzing step is carried out by PCR.

5. The method according to claim 3 , wherein when the cancerous sample expresses mRNA level of MUC1 gene, NME7 gene or NME7-X1 gene that is at least 0.5% of the mRNA expression level of EEF1A1 gene, it is determined to be MUC1* positive, NME7 AB positive or NME7-X1 positive.

6. The method according to claim 3 , wherein the analyzing step is carried out by immunohistochemistry.

7. The method according to claim 6 , wherein when the cancerous sample is contacted with an antibody that binds to the PSMGFR peptide or the N-10 peptide and stains the tissue with a pathologist's standard score 1-4 (“+-++++”), it is determined to be MUC1* positive.

8. The method according to claim 6 , wherein when the cancerous sample is contacted with an antibody that binds to the B3 peptide of NME7 and stains the tissue with a pathologist's standard score 1-4 (“+-++++”), it is determined to be NME7 AB positive or NME7-X1 positive.

9. The method of claim 1 , comprising administering to the subject the compound of Formula 5:

10. The method of claim 9 , wherein in Formula 5, R1 an optionally substituted C1-C6 alkyl or an optionally substituted C3-C8 cycloalkyl.

11. The method of claim 1 , comprising administering to the subject the compound of Formula 6:

12. The method of claim 11 , wherein in Formula 6, R1 is optionally substituted C1-C6 alkyl or optionally substituted C3-C8 cycloalkyl.

13. The method of claim 1 , comprising administering to the subject the compound of Formula 7:

wherein,

R1 is H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C1-C9 heteroaryl with 1 to 4 ring atoms independently selected from N, S, and O, optionally substituted C7-C15 arylalkyl, optionally substituted C2-C15 heteroarylalkyl with 1 to 4 ring atoms independently selected from N, S, and O, optionally substituted C7-C15 arylalkenyl, an optionally substituted C3-C8 cycloalkyl, or optionally substituted C4-C8 cycloalkylalkyl.

14. The method of claim 13 , wherein in Formula 7, R1 is H, an optionally substituted C1-C6 alkyl, or an optionally substituted C3-C8 cycloalkyl.

15. The method of claim 13 , wherein in Formula 7,

R1 is hydrogen, methyl, ethyl, isopropyl, isobutyl, benzyl, or pyridyl;

R2 is hydrogen, halogen, methyl or methoxy;

Z2 is O, NH, or —CH2—;

G2 is —CH2—, —(CH2)2—, —(CH2)3—, —(CH2)4—, —CH2NHCO— or —cyclohexylene—;

R5 is hydrogen, or methyl; and

X is hydrogen or methyl.

16. The method of claim 1 , comprising administering to the subject the compound of Formula 9:

wherein,

R1 is H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally C1-C9 heteroaryl with 1 to 4 ring atoms independently selected from N, S, and O, optionally substituted C7-C15 arylalkyl, optionally substituted C2-C15 heteroarylalkyl with 1 to 4 ring atoms independently selected from N, S, and O, optionally substituted C7-C15 arylalkenyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted C4-C8 cycloalkylalkyl.

17. The method of claim 16 , wherein in Formula 9, R1 is H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C8 cycloalkyl.

18. The method of claim 16 , wherein in Formula 9,

R1 is isopropyl or isobutyl;

R2 is hydrogen, halogen, or methyl;

Z2 is O or NH;

R5 is hydrogen; and

X is methyl.

19. A compound of Formula 5, Formula 6, Formula 7, or Formula 9,

wherein,

R1 is H, optionally substituted C1-C6 alkyl or an optionally substituted C3-C8 cycloalkyl;

G1 is —(CH 2 ) n —, —CH═CH—, or —C3-C7 cycloalkylene-CH 2 —;

Z2 is a bond, —NH—, —O—, —S—, —CH(CH 3 )—, —(CH 2 ) n —, —CH═CH—, —CO—, —SO—, —SO 2 —, —C(═NH)—, —CH 2 NH(CO)—, —CH 2 NH(CO)O—, —CH 2 NH(CO)NH—, —(CH 2 ) p NH(CO)—, —(CH 2 ) p NH(CO)O—, —(CH 2 ) p NH(CO)NH—, —C3-C7 cycloalkylene-NH(CO)—, —C3-C7 cycloalkylene-CH 2 NH(CO)O—, —C3-C7 cycloalkylene-NH(CO)NH—, —N(CH 2 CH 2 C 6 H 4 )—, or optionally substituted C6-C12 arylene;

R5 is H, C1-C6 alkyl, or 2-phenylethyl;

R4 is H, optionally substituted C1-C9 alkyl, optionally substituted C2-C6 alkenyl; optionally substituted C6-C12 aryl, optionally substituted C1-C9 heteroaryl with 1 to 4 ring atoms independently selected from N, S, and O, optionally substituted C7-C15 arylalkyl, optionally substituted C3-C7 cycloalkyl, —(CH 2 ) p —NH(CO)O—(C1-C6 alkyl), —CH 2 O(CH 2 ) p —NH(CO)O—(C1-C6) alkyl, —(CH 2 ) p —NHCO—(CH 2 ) n —NH(CO)O—C1-C6 alkyl), —NH(CO)O-tert-butyl, —O-tert-butyl, or -tert-butyl;

each n is independently selected from 1-8; each p is independently elected from 1-9;

wherein,

R1 is H, C1-C6 alkyl, or optionally substituted C3-C8 cycloalkyl,

G1 is —(CH 2 )n—, —CH═CH—, or —C3-C7 cycloalkylene-CH 2 —;

R5 is H, C1-C6 alkyl, or 2-phenylethyl;

X is H, or C1-C3 alkyl;

each n is independently selected from 1-8; each p is independently selected from 1-9;

wherein,

R1 is H, C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C9 heteroaryl with 1 to 4 ring atoms independently selected from N, S, and O, optionally substituted C7-C15 arylalkyl, optionally substituted C2-C15 heteroarylalkyl with 1 to 4 ring atoms independently selected from N, S, and O, optionally substituted arylalkenyl, an optionally substituted C3-C8 cycloalkyl, or optionally substituted C4-C8 cycloalkylalkyl;

G2 is a bond, —(CH 2 ) n —, —CH═CH—, —CH 2 NH(CO)—, —CH 2 NH(CO)O—, —CH 2 NH(CO)NH—, —(CH 2 ) n NH(CO)—, —(CH 2 ) n NH(CO)O—, —(CH 2 ) m NH(CO)NH—, or —C3-C7 cycloalkyl—,

Z2 is a bond, —NH, —O—, —S—, —CH(CH 3 )—, —(CH 2 ) n —, —CH═CH—, —CO—, —SO—, —SO 2 — or —C(═NH)—, —CH 2 NH(CO)—, —CH 2 NH(CO)O—, —CH 2 NH(CO)NH—, —(CH 2 ) p NH(CO)—, —(CH 2 ) p NH(CO)O—, —(CH 2 ) p NH(CO)NH—, —C3-C7 cycloalkylene-NH(CO)—, —C3-C7 cycloalkylene-CH 2 NH(CO)O—, —C3-C7 cycloalkylene-NH(CO)NH—, or —N(CH 2 CH 2 C 6 H 5 )—;

R5 is H, C1-C6 alkyl, or 2-phenylethyl;

X is H, or C1-C3 alkyl;

each m is independently selected from 1-5; each n is independently selected from 1-8; each p is independently selected from 1-9;

where “substituted” means substituted with one or more substituents independently selected from halogen, trifluoromethyl, methylcarboxy, ethylcarboxy, C1-C6 alkoxy, C1-C6 alkyl, —OH, —SH, —NH 2 , - N 3 , —CN, —NO 2 , —CHO, —COOH, —CONH 2 , —C(═NH)NH 2 , or —SO 3 H;

wherein,

R5 is H, C1-C6 alkyl, or 2-phenylethyl;

X is H, or C1-C3 alkyl;

Z2 is a bond, —NH—, —O—, —S—, —CH(CH 3 )—, —(CH 2 ) n —, —CH═CH—, —CO—, —SO—, —SO 2 — or —C(═NH)—, —CH 2 NH(CO)—, —CH 2 NH(CO)O—, —CH 2 NH(CO)NH—, —(CH 2 ) n NH(CO)—, —(CH 2 ) n NH(CO)O—, —(CH 2 ) m NH(CO)NH—, —C3-C7 cycloalkylene-NH(CO)—, —C3-C7 cycloalkylene-CH 2 NH(CO)O—, —C3-C7 cycloalkylene-NH(CO)NH—, or —N(CH 2 CH 2 C 6 H 4 )—,

each p is independently selected from 1-5; each n is independently selected from 1-8;

20. The method according to claim 1 , wherein the compound is selected from the group consisting of:

21. A compound selected from the group consisting of:

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 7, 2018

From: BAMDAD, CYNTHIA; MOE, SCOTT

To: MINERVA BIOTECHNOLOGIES CORPORATION

Reel/Frame 047712/0242 →

Continuity (2)

Provisional Application 62222713 · Sep 23, 2015

Related Publication 20180263964A1 · Sep 20, 2018

Cited By (5)

US 12,202,799 US 12,295,959 US 12,415,868 US 12,491,259 US 12,630,512