) ( (51) International Patent Classification: Declarations under Rule 4.17: A61K 33/36 (2006.01) A61P 35/02 (2006.01) — as to applicant's entitlement to apply for and be granted a A61P 35/00 (2006.01) patent (Rule 4.17(H)) (21) International Application Number: — as to the applicant's entitlement to claim the priority of the PCT/CN20 19/070 117 earlier application (Rule 4.17(iii)) — of inventorship (Rule 4.17(iv)) (22) International Filing Date: 02 January 2019 (02.01.2019) Published: — with international search report (Art. 21(3)) (25) Filing Language: English (26) Publication Language: English (30) Priority Data: PCT/CN20 18/07005 1 02 January 2018 (02.01.2018) CN PCT/CN20 18/085 190 28 April 2018 (28.04.2018) CN (71) Applicant: RUI JIN HOSPITAL, SHANGHAI JIAO TONG UNIVERSITY SCHOOL OF MEDICINE [CN/CN]; 11th Building, 197 Ruijin Er Road, Shanghai 200025 (CN). (72) Inventors: LU, Min; 1lth Building, 197 Ruijin Er Road, Shanghai 200025 (CN). WU, Jiale; 11th Building, 197 Rui¬ jin Er Road, Shanghai 200025 (CN). SONG, Huaxin; 11th Building, 197 Ruijin Er Road, Shanghai 200025 (CN). (74) Agent: BEIJING DACHENG LAW OFFICES, LLP; 15th/16th Floor, Shanghai Tower, 501 YinchengRoad (M), Pudong New Area, Shanghai 200120 (CN). (81) Designated States (unless otherwise indicated, for every kind of national protection available) : AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (84) Designated States (unless otherwise indicated, for every kind of regional protection available) : ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, Cl, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). (54) Title: MP53 RESCUE COMPOUNDS AND METHODS OF TREATING A P53 DISORDER (57) Abstract: Novel mp53 rescue compounds and the pharmaceutical composition, and methods of treating a p53 disorder. MP53 RESCUE COMPOUNDS AND METHODS O F TREATING A P53 DISORDER TECHNICAL FIELD [0001] Various compositions for the rescue of a mp53, various pharmaceutical composition for a p53 disorder, such as cancer, and various methods for treating the p53 disorder, are disclosed herein. CROSS REFERENCE TO RELATED APPLICATIONS [0002] This application claims priority to International Application No. PCT/CN201 8/070051 filed on January 2 , 2018, entitled “PANDA AS A NOVEL THERAPEUTIC and International Application No. PCT/CN/201 8/0851 90 filed on April 28, 2018, entitled “PANDA A S A NOVEL THERAPEUTIC,” the content of each application is incorporated herein by reference in their entirety. BACKGROUND [0003] Various compounds for rescuing mp53 and treating a p53 disorder, including cancer, and various methods of treating a p53 disorder have been proposed. Because these compounds, treatments and methods of treatments are not optimal, there is a need in the field for improved mp53 rescue compounds, treatments for a p53 disorder, and methods of treating a p53 disorder. SUMMARY [0004] W e have described herein compounds that have one or more useful characteristic(s) and can form one or more tight assodation(s) with a PANDA Pocket (each compound a “PANDA Agenf)· In certain embodiments, the PANDA Agent can regulate the level of one or more p53 target gene. Exemplary target genes include Apafl, Bax, Fas, Dr5, mir-34, Noxa, TP53AIP1, Parp, Pidd, Pig3, Puma, Siva, YWHAZ, Btg2, Cdknla, Mdm2, Tp53i3, Gadd45a, mir-34a, mir-34b/34c, Pr13, Ptprv, Raprimo, Pail, Pml, Ddb2, ErccS, Fancc, Gadd45a, Ku86, Mgmt, Mlh1, Msh2, P53r2, Polk, Xpc, Adora2b, Aldh4, Garni, Gls2, Gpx1, Lpinl, Parkin, Prkabl, Prkab2, Ptan, S∞ 1, Sasnl, Sesn2, Tigar, Tp53inp1, Tsc2, Atg10, Atg2b, Atg4a, Atg4c, Atg7, Ctsd, Ddit4, Draml, Foxo3, Laptm4a, Lkb1, Pik3r3, Prkag2, Puma, Tpp1, Tsc2, Ulk1, Ulk2, Uvrag, Vamp4, Vmp1, Bail, Cx3cl1, lcaml, irfS, lr†9, Isg15, Maspin, Mcp1, Ncf2, Pail, Tlr1-Tlr10, Tsp1, Ulbpl, Ulbp2, mir-34a, mir-200c, mir-145, mir-34a, mir-34b/34c, Notchl, combinations thereof and the like. In certain embodiments, the tight association formed by PANDA Agent and PANDA Pocket substantially stabilizes p53. Preferably, the tight association increases the Tm of p53 at least by about 0.5°C, more preferably at least by about 1°C, further preferably at least by about 2°C, further preferably at least by about 5°C, further preferably at least to about 8°C. In certain embodiments, the tight association formed by PANDA Agent and PANDA Pocket increases the population of properly folded p53 at least to about 1.5 times, preferably at least to about 3 times, more preferably at least to about 5 times, more preferably at least to about 10 times, and further preferably to about 100 times. In preferred embodiments, the increase is measured to a PAb1620 immunoprecipitation assay. [0005] In certain embodiments, the PANDA Agent includes one or more PANDA Pocket¬ binding groups capable of binding one or more amino acids on PANDA Pocket, preferably one or more cysteines, more preferably two or more cysteines, further preferably more than three cysteines, further preferably from about three cysteines to about 6 cysteines. The PANDA Pocket binding group is preferred to include metallic group(s), metalloid group(s), and other group(s) capable of binding to PANDA Pocket such as Michael acceptor(s) and thiol group(s). The PANDA Pocket-binding groups is further preferred to include one or more arsenic, antimony, and bismuth, including any analogue(s) thereof, and any combinations thereof. Exemplary PANDA Pocket-binding groups include compounds containing a 3- valence and/or 5-valence arsenic atom, a 3-valence and/or 5-valence antimony atom, a 3- valence and/or 5-valence bismuth atom, and/or a combination thereof. [0006] Exemplary embodiments of a PANDA Agent can include any one of the following Formulas l-XV. wherein: M is an atom selected from a group consisting of As, Sb, and Bi; Z is a functional group comprising a non-Carbon atom that forms a bond with M, wherein the non-Carbon atom is preferably selected from the group consisting of H, D, F, Cl, Br, I, O, S, Se, Te, Li, Na, K, Cs, Mg, Cu, Zn, Ba, Ta, W, Ag, Cd, Sn, X, B, N, P, Al, Ga, In, Tl, Ni, Si, Ge, Cr, Mn, Fe, Co, Pb, Y, La, Zr, Nb, Pr, Nd, Sm, Eu, Gd, Dy, Tb, Ho, Er, Tm, Yb, and Lu; wherein: R1 is selected from 1 to 9 X groups; R2 is selected from 1 to 7 X groups; R3 is selected from 1 to 8 X groups; and wherein each X group comprises an atom that forms a bond with M; and wherein: each of M, the non-Carbon atom, and the atom has the appropriate charge, including no charge, in the compound; each of Z and X is independently selected and can be the same or different from the other Z or X in the compound, respectively; and each of the M, non-Carbon atom and the atom can be a part of a ring member. In the preferred embodiment, the non-Carbon atom is selected from the group consisting of O, S, N, X, F, Cl, Br, I, and H. [0007] The following Equation ( 1) is an reaction for PANDA Agent. A compound containing M group with a Z 1 (a first group with the capacity to bind a first cysteine) and/or a Z2 (a second group with the capacity to bind a second cysteine) and/or a Z3 (a third group with the capacity to bind a third cysteine), Examples of Zi, Z2, and Z 3 includes O, S, N, X, F, Cl, Br, I, OH, and H. Zi, Z2, and/or Z 3 can bind to each other. M group includes for example a metal, such as an bismuth, a metalloid, such as an arsenic and an antimony, a group such as a Michael acceptor and/or a thiol, and/or any analogue with cysteine-binding ability. The PANDA Agent can undergo a hydrolysis before reacting and binding to p53 forming PANDA. In some cases, when a group cannot undergo hydrolysis, and accordingly cannot bind to a cysteine. In such cases, the remaining group(s) with cysteine binding potential binds to p53. Xi and X 2 represent any groups bound to M. X 1 and/or X2 can also be empty. X 1 and/or X2 can also be able to bind cysteine. [0008] [0009] The following Equations (2) and (3) is an exemplary reaction for a PANDA Agent with tri-cysteine binding potential. 3-valence ATO or KAsO2 undergoes hydrolysis, covalently binds to three PANDA Cysteines on p53. [0010] [0011] [0012] The following equation (4) is an exemplary reaction for a PANDA Agent with tri- cysteine binding potential. 5-valence As compound undergoes hydrolysis, covalently binds to three PANDA Cysteines on p53.