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US-20260125362-A1 - TARGETED PROTEIN DEGRADATION OF PARP14 FOR USE IN THERAPY

US20260125362A1US 20260125362 A1US20260125362 A1US 20260125362A1US-20260125362-A1

Abstract

The present invention relates to quinazolinones and related compounds which degrade PARP14 and are useful, for example, in the treatment of cancer and inflammatory diseases.

Inventors

  • Laurie B. Schenkel
  • Melissa Marie Vasbinder
  • Kevin Wayne Kuntz
  • Kerren Kalai Swinger
  • Timothy J.N. WIGLE

Assignees

  • ABBVIE BIOTECHNOLOGY LTD

Dates

Publication Date
20260507
Application Date
20250522

Claims (20)

  1. 1 . A compound of Formula (A1): or a pharmaceutically acceptable salt thereof, wherein: Q is a moiety represented by Formula I: wherein: W is CR W or N; X is CR X or N; Y is CR or N; Z is CR Z or N; wherein no more than two of W, X, Y, and Z are simultaneously N; Ring A is monocyclic or polycyclic C 3-14 cycloalkyl or Ring A is monocyclic or polycyclic 4-18 membered heterocycloalkyl, wherein Ring A is optionally substituted by 1, 2, 3, or 4 R A , and Ring A is attached to the —(L) m -moiety of Formula I through a non-aromatic ring when Ring A is polycyclic; L is —(CR 5 R 6 ) t —, —(CR 5 R 6 ) p —, O—(CR 5 R 6 ) q , —(CR 5 R 6 ) p —, S—(CR 5 R 6 ) q —, —(CR 5 R 6 ) p —NR 3 —(CR 5 R) q —, —(CR 5 R 6 ) p , —CO—(CR 5 R 6 ) q —, —(CR 5 R 6 ) r —C(O)O—(CR 5 R 6 ) 5 —, —(CR 5 R 6 ) r —CONR 3 —(CR 5 R 6 ) s —, —(CR 5 R 6 ) p —SO—(CR 5 R 6 ) q —, —(CR 5 R 6 ) p —SO 2 —(CR 5 R 6 ) q —, —(CR 5 R 6 ) r —SONR 3 —(CR 5 R 6 ) s —, or —NR 3 CONR 4 -; R 1 and R 2 are each, independently, selected from H and methyl; R 3 and R 4 are each, independently, selected from H and C 1-4 alkyl; R 5 and R 6 are each, independently, selected from H, halo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, amino, C 1-4 alkylamino, and C 2-8 dialkylamino; each R A is independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R 1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R c1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , C(═NR c1 )R 1 , C(═NR c1 )NR c1 R d1 , NR c1 C(═NR c1 )NR c1 R d1 , NR c1 S(O)R d1 , NR c1 S(O) 2 RI, NR c1 S(O) 2 NR c1 R d1 , S(O)R 1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, and 4-10 membered heterocycloalkyl-C 1-4 alkyl of R A are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy 1 , Cy 1 -C 1-4 alkyl, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R 1 , OC(O)NR c1 R d1 , C(═NR c1 )NR c1 R d1 , NR c1 C(═NR c1 )NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O) 2 R b1 , NR c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 ; R W , R X , R Y , and R Z are each, independently, selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO 2 , OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , C(═NR e2 )R b2 , C(═NR e2 )NR c2 R d2 , NR c2 C(═NR e2 )NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O) 2 R b2 , NR c2 S(O) 2 NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, and 4-10 membered heterocycloalkyl-C 1-4 alkyl of R W , R X , R Y , or R Z are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy 2 , Cy 2 -C 1-4 alkyl, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO 2 , OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , C(═NR e2 )NR c2 R d2 , NR c2 C(═NR e2 )NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O) 2 R b2 , NR c2 S(O) 2 NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ; wherein when W is CR W , X is CR X , Y is CR Y , and Z is CR Z , then at least one of R W , R X , R Y , and R Z is other than H; each Cy 1 is independently selected from C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, or 4 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO 2 , OR a1 , SR a1 , C(O)R 1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R 1 , OC(O)NR c1 R d1 , C(═NR c1 )NR c1 R d1 , NR c1 C(═NR c1 )NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R a1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)R d1 , NR c1 S(O) 2 R b1 , NR c1 S(O) 2 NR c1 R d1 , S(O)R 1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 ; each Cy 2 is independently selected from C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, or 4 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO 2 , OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , C(═NR e2 )NR c2 R d2 , NR c2 C(═NR e2 )NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O) 2 R b2 , NR c2 S(O) 2 NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ; each R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , and R d2 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, and 4-10 membered heterocycloalkyl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, and 4-10 membered heterocycloalkyl-C 1-4 alkyl of R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , or R d2 is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy 3 , Cy 3 -C 1-4 alkyl, halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR a3 , C(═NR e3 )NR c3 R d3 , NR c3 C(═NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , NR c3 S(O) 2 R b3 , NR c3 S(O) 2 NR c3 R d3 , and S(O) 2 NR c3 R d3 ; each Cy 3 is C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, or 4 substituents independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R b3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR a3 , C(═NR e3 )NR c3 R d3 , NR c3 C(═NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , NR c3 S(O) 2 R b3 , NR c3 S(O) 2 NR c3 R d3 , and S(O) 2 NR c3 R d3 ; R a3 , R b3 , R c3 , and R d3 are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, and 4-10 membered heterocycloalkyl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, and 4-10 membered heterocycloalkyl-C 1-4 alkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy; or R c1 and R d1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, CN, OR a3 , SR a3 , C(O)R b3 , C(O)NR 3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR a3 , C(═NR e3 )NR c3 R d3 , NR c3 C(═NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R c3 , NR c3 S(O) 2 R c3 , NR c3 S(O) 2 NR c3 R d3 , and S(O) 2 NR c3 R d3 ; or R c2 and R d2 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, CN, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR a3 , C(═NR e3 )NR c3 R d3 , NR c3 C(═NR e3 )NR c3 R d3 , S(O)R 3 , S(O)NR c3 R d3 , S(O) 2 R c3 , NR c3 S(O) 2 R b3 , NR c3 S(O) 2 NR c3 R d3 , and S(O) 2 NR c3 R d3 ; each R c1 , R e2 , and R e3 is independently selected from H, C 1-4 alkyl, and CN; m is 0 or 1, n is 0, 1, or 2; p is 0, 1, or 2; q is 0, 1, or 2, wherein p+q is 0, 1, or 2; r is 0 or 1; s is 0 or 1, where r+s is 0 or 1; and t is 1, 2, or 3; L 1 is a linker, which is covalently linked to moiety Q and to moiety E; E is an E3 ubiquitin ligase binding moiety, which binds to the E3 ubiquitin ligase; and wherein the wavy lines represent the points of attachment to group L 1 ; wherein any aforementioned heteroaryl or heterocycloalkyl group comprises 1, 2, 3, or 4 ring-forming heteroatoms independently selected from O, N, and S; wherein one or more ring-forming C or N atoms of any aforementioned heterocycloalkyl group is optionally substituted by an oxo (═O) group; and wherein one or more ring-forming S atoms of any aforementioned heterocycloalkyl group is optionally substituted by one or two oxo (═O) groups.
  2. 2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein linker L 1 is a chain of 1 to 40, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, or 1 to 5 chain atoms, which is optionally substituted with 1-3 R q substituents, and wherein one or more chain carbon atoms of U can be oxidized to form a carbonyl (C═O), and wherein one or more N and S chain atoms can each be optionally oxidized to form an amine oxide, sulfoxide or sulfonyl group; and each R q is independently selected from OH, CN, —COOH, NH 2 , halo, C 1-6 haloalkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C 3-6 cycloalkyl, NH(C 1-6 alkyl) and N(C 1-6 alkyl) 2 , wherein the C 1-6 alkyl, phenyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl of R q are each optionally substituted with halo, OH, CN, —COOH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, phenyl, C 3-10 cycloalkyl, 5- or 6-membered heteroaryl or 4-6 membered heterocycloalkyl.
  3. 3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein linker L 1 has the structure: wherein each G is independently selected from —C(O)—, —NR G C(O)—, —NR G —, —O—, —S—, —C(O)O—, —OC(O)NR G —, —NR G C(O)NR G —, —S(O 2 )—, or —S(O)NR G —; each R G is independently selected from H, methyl, and ethyl; a is 0 or 1; b is 0 or 1; and c is 0 or 1, wherein the wavy lines represent points of attachment to moieties Q and E.
  4. 4 . The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein a is 1, b is 1, and c is 1.
  5. 5 . The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein a is 0, b is 1, and c is 0.
  6. 6 . The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein a is 1, b is 1, and c is 0.
  7. 7 . (canceled)
  8. 8 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein linker L 1 is selected from: wherein the wavy lines represent points of attachment to moieties Q and E.
  9. 9 - 44 . (canceled)
  10. 45 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Q is a moiety having Formula II: wherein the wavy lines represent the point of attachment to group L 1 .
  11. 46 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Q is a moiety having Formula IIIA, IIIB, IIIC, HID, or IIIE: wherein the wavy lines represent the point of attachment to group L 1 .
  12. 47 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Q is a moiety having Formula IVA or IVB: wherein the wavy lines represent the point of attachment to group L 1 .
  13. 48 . The compound of claim 1 , having Formula (A2): or a pharmaceutically acceptable salt thereof.
  14. 49 . The compound of claim 1 , having Formula (A3): or a pharmaceutically acceptable salt thereof.
  15. 50 . The compound of claim 1 , having Formula (A4): or a pharmaceutically acceptable salt thereof.
  16. 51 . The compound of claim 1 , having Formula (A5): or a pharmaceutically acceptable salt thereof.
  17. 52 . The compound of claim 1 , having Formula (A6): or a pharmaceutically acceptable salt thereof.
  18. 53 . The compound of claim 1 , wherein the compound is selected from the following: or a pharmaceutically acceptable salt of any of the aforementioned.
  19. 54 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  20. 55 . (canceled)

Description

FIELD OF THE INVENTION The present invention relates to quinazolinones and related compounds which cause intracellular proteolysis of PARP14 and are useful in the treatment of cancer and inflammatory diseases. BACKGROUND OF THE INVENTION Poly(ADP-ribose) polymerases (PARPs) are members of a family of seventeen enzymes that regulate fundamental cellular processes including gene expression, protein degradation, and multiple cellular stress responses (Vyas S, et al. Nat Rev Cancer. 2014 Jun. 5; 14(7):502-509). The ability of cancer cells to survive under stress is a fundamental cancer mechanism and an emerging approach for novel therapeutics. One member of the PARP family, PARP1, has already been shown to be an effective cancer target in connection to cellular stress induced by DNA damage, either induced by genetic mutation or with cytotoxic chemotherapy, with three approved drugs in the clinic and several others in late stage development (Ohmoto A, et al. OncoTargets and Therapy. 2017; Volume 10:5195). The seventeen members of the PARP family were identified in the human genome based on the homology within their catalytic domains (Vyas S, et al. Nat Commun. 2013 Aug. 7; 4:2240). However, their catalytic activities fall into 3 different categories. The majority of PARP family members catalyze the transfer of mono-ADP-ribose units onto their substrates (monoPARPs), while others (PARP1, PARP2, TNKS, TNKS2) catalyze the transfer of poly-ADP-ribose units onto substrates (polyPARPs). Finally, PARP13 is thus far the only PARP for which catalytic activity could not be demonstrated either in vitro or in vivo. PARP14 is a cytosolic as well as nuclear monoPARP. It was originally identified as BAL2 (B Aggressive Lymphoma 2), a gene associated with inferior outcome of diffuse large B cell lymphoma (DLBCL), together with two other monoPARPs (PARP9 or BAL1 and PARP15 or BAL3) (Aguiar R C, et al. Blood. 2000 Dec. 9; 96(13):4328-4334 and Juszczynski P, et al. Mol Cell Biol. 2006 Jul. 1; 26(14):5348-5359). PARP14, PARP9 and PARP15 are also referred to as macro-PARPs due to the presence of macro-domains in their N-terminus. The genes for the three macroPARPs are located in the same genomic locus suggesting co-regulation. Indeed, the gene expression of PARP14 and PARP9 is highly correlated across normal tissues and cancer types. PARP14 is overexpressed in tumors compared to normal tissues, including established cancer cell lines in comparison to their normal counterparts. Literature examples of cancers with high PARP14 expression are DLBCL (Aguiar R C T, et al. J Biol Chem. 2005 Aug. 1; 280(40):33756-33765), multiple myeloma (MM) (Barbarulo A, et al. Oncogene. 2012 Oct. 8; 32(36):4231-4242) and hepatocellular carcinoma (HCC) (Iansante V, et al. Nat Commun. 2015 Aug. 10; 6:7882). In MM and HCC cell lines RNA interference (RNAi) mediated PARP14 knockdown inhibits cell proliferation and survival. Other studies show that the enzymatic activity of PARP14 is required for survival of prostate cancer cell lines in vitro (Bachmann S B, et al. Mol Cancer. 2014 May 27; 13:125). PARP14 has been identified as a downstream regulator of IFN-γ and IL-4 signaling, influencing transcription downstream of STAT1 (in the case of IFN-γ) (Iwata H, et al. Nat Commun. 2016 Oct. 31; 7:12849) or STAT6 (in the case of IL-4) (Goenka S, et al. Proc Natl Acad Sci USA. 2006 Mar. 6; 103(11):4210-4215; Goenka S, et al. J Biol Chem. 2007 May 3;282(26):18732-18739; and Mehrotra P, et al. J Biol Chem. 2010 Nov. 16; 286(3):1767-1776). Parp14 −/− knockout (KO) mice have reduced marginal zone B cells, and the ability of IL-4 to confer B cell survival in vitro was reduced as well in the Parp14 KO setting (Cho S H, et al. Blood. 2009 Jan. 15; 113(11):2416-2425). This decreased survival signaling was linked mechanistically to decreased abilities of Parp14 KO B cells to sustain metabolic fitness and to increased Mcl-1 expression. Parp14 KO can extend survival in the E-Myc lymphoma model, suggesting a role of PARP14 in Myc-driven lymphomagenesis (Cho S H, et al. Proc Natl Acad Sci USA. 2011 Sep. 12; 108(38):15972-15977). Gene expression data point towards roles of PARP14 in human B cell lymphoma as well. The BAL proteins, including PARP14, are highly expressed in host response (HR) DLBCLs, a genomically defined B cell lymphoma subtype characterized with a brisk inflammatory infiltrate of T and dendritic cells and presence of an IFN-γ gene signature (Molecular profiling of diffuse large B-cell lymphoma identifies robust subtypes including one characterized by host inflammatory response. Monti S, et al. Blood. 2005;105(5):1851). Indeed, PARP14 is believed to be an interferon stimulated gene with its mRNA increased by stimulation of various cell systems with all types of interferon (I, II and III; www.interferome.org). Due to its role downstream of IL-4 and IFN-γ signaling pathways PARP14 has been implicated in T helper cell and macrophage differentiation. Genetic PARP14 inac